Novel substituted indolines with an inhibitory effect on various kinases and complexes of CDKs

ABSTRACT

The present invention relates to new substituted indolinones of general formula  
                 
 
     wherein  
     X and R 1  to R 5  are defined as in claim 1, the isomers and the salts thereof which have valuable properties.  
     The above compounds of general formula I wherein R 1  denotes a hydrogen atom, a C 1-3 -alkyl group or a prodrug group have valuable pharmacological properties, particularly an inhibiting effect on various kinases, on viral cyclin and on receptor tyrosine kinases, and the other compounds of the above general formula I wherein R 1  does not represent a hydrogen atom, a C 1-3 -alkyl group or a prodrug group are valuable intermediate products for the preparation of the abovementioned compounds.

[0001] The present invention relates to new substituted indolinones ofgeneral formula

[0002] the isomers thereof, the salts thereof, particularly thephysiologically acceptable salts thereof which have valuable properties.

[0003] The above compounds of general formula I wherein R₁ denotes ahydrogen atom, a C₁₋₃-alkyl group or a prodrug group have valuablepharmacological properties, particularly an inhibiting effect on variouskinases, especially on complexes of CDKs (CDK1, CDK2, CDK3, CDK4, CDK6,CDK7, CDK8 and CDK9) with their specific cyclins (A, B1, B2, C, D1, D2,D3, E, F, G1, G2, H, I and K), on viral cyclin (cf. L. Mengtao in J.Virology 71(3), 1984-1991 (1997)), and on receptor tyrosine kinases suchas HER2, EGFR, FGFR, IGF-1R and KDR, and the other compounds of theabove general formula I wherein R₁ does not represent a hydrogen atom, aC₁₋₃-alkyl group or a prodrug group are valuable intermediate productsfor the preparation of the above-mentioned compounds which have usefulpharmacological properties.

[0004] The present invention thus relates to the above compounds ofgeneral formula I, in which the compounds wherein R₁ denotes a hydrogenatom, a C₁₋₃-alkyl group or a prodrug group such as aC₁₋₄-alkoxycarbonyl or C₂₋₄-alkanoyl group have valuable pharmacologicalproperties, the pharmaceutical compositions containing thepharmacologically active compounds, their use and processes forpreparing them.

[0005] In the above general formula I

[0006] X denotes an oxygen or sulphur atom,

[0007] R₁ denotes a hydrogen atom, C₁₋₃-alkyl or hydroxy group,

[0008] R₂ denotes a hydrogen, fluorine, chlorine, bromine or iodineatom, a C₁₋₃-alkyl or nitro group,

[0009] R₃ denotes a phenyl or naphthyl group, each of which may be mono-or disubstituted by fluorine, chlorine, bromine or iodine atoms, byC₁₋₃-alkyl, C₁₋₃-alkoxy, carboxy, cyano, trifluoromethyl, nitro, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, C₁₋₃-alkylsulphonylamino,amino-C₁₋₃-alkyl, 2-carboxy-phenylcarbonylaminomethyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, C₂₋₄-alkanoylamino-C₁₋₃-alkyl,N-(C₂₋₄-alkanoyl)-C₁₋₃-alkylamino-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, carboxy-C₂₋₃-alkenyl,N-(carboxy-C₁₋₃-alkyl)-aminocarbonyl,N-(carboxy-C₁₋₃-alkyl)-N-(C₁₋₃-alkyl)-aminocarbonyl orimidazolyl-C₁₋₃-alkyl groups, while the substituents may be identical ordifferent,

[0010] R₄ denotes a hydrogen atom or a C₁₋₃-alkyl group and

[0011] R₅ denotes a phenyl or naphthyl group optionally substituted by aC₁₋₃-alkyl group, each of which may additionally be substituted in thearomatic moiety

[0012] by a fluorine, chlorine, bromine or iodine atom, by a C₁₋₃-alkyl,C₁₋₃-alkoxy, cyano, nitro or trifluoromethyl group,

[0013] by a C₁₋₃-alkoxy group which is substituted by a carboxy,aminocarbonyl, C₁₋₃-alkylaminocarbonyl or di-(C₁₋₃-alkyl)-aminocarbonylgroup or in the 2 or 3 position by an amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, phenyl-C₁₋₃-alkylamino,N-(phenyl-C₁₋₃-alkyl)-N-(C₁₋₃-alkyl)-amino, pyrrolidino, piperidino orhexamethyleneimino group,

[0014] by a C₂₋₃-alkenyl group optionally substituted by adi-(C₁₋₃-alkyl)-amino group, which may additionally be substituted inthe alkenyl moiety by a chlorine or bromine atom,

[0015] by a C₂₋₃-alkynyl group optionally substituted by adi-(C₁₋₃-alkyl)-amino group,

[0016] by a C₁₋₃-alkyl group which is substituted by a 3- to 7-memberedcycloalkyleneimino group, by a dehydropiperidino, morpholino,thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino,piperazino, N-(C₁₋₃-alkyl)-piperazino, N-(C₁₋₃-alkanoyl)-piperazino orN-(C₁₋₅-alkoxycarbonyl)-piperazino group, whilst the above-mentionedsubstituents may be substituted by a C₁₋₃-alkyl, phenyl orphenyl-C₁₋₃-alkyl group and the abovementioned piperidino orhexamethyleneimino groups may additionally be substituted by aC₁₋₃-alkyl group or in the 3 or 4 position by a hydroxy, C₁₋₃-alkoxy,hydroxy-C₁₋₃-alkyl, carboxy, aminocarbonyl, N-(C₁₋₃-alkyl)-aminocarbonylor N,N-di-(C₁₋₃-alkyl)-aminocarbonyl group,

[0017] by a C₁₋₃-alkyl group substituted by a hydroxy, C₁₋₃-alkoxy,carboxy or cyano group, whilst a C₁₋₃-alkyl group substituted by acarboxy group may additionally be substituted in the alkyl moiety by anamino or C₁₋₅-alkoxycarbonylamino group,

[0018] by an aminocarbonylamino, amidino or guanidino group optionallysubstituted by one or two C₁₋₃-alkyl groups,

[0019] by a piperidino, hexamethyleneimino, morpholino, piperazino orN-(C₁₋₃-alkyl)-piperazino group,

[0020] by a formyl, carboxy or trifluoroacetyl group,

[0021] by a carbonyl group which

[0022] is substituted by a C₁₋₃-alkyl, C₁₋₃-alkoxy-C₁₋₃-alkyl, amino,C₁₋₅-alkylamino or di-(C₁₋₃-alkyl)-amino group, while the abovementionedamino and C₁₋₃-alkylamino groups may additionally be substituted at thenitrogen atom by a carboxy-C₁₋₃-alkyl group or by a C₂₋₃-alkyl groupwhich is substituted in the 2 or 3 position by a hydroxy, C₁₋₃-alkoxy,amino, C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-amino group,

[0023] by a pyrrolidinocarbonyl, piperidinocarbonyl,hexamethyleneiminocarbonyl, morpholinocarbonyl, piperazinocarbonyl,N-(C₁₋₃-alkyl)-piperazinocarbonyl orN-(phenyl-C₁₋₃-alkyl)-piperazinocarbonyl group,

[0024] by an amidosulphonyl, pyrrolidinosulphonyl, piperidinosulphonylor hexamethyleneiminosulphonyl group, by a C₁₋₃-alkylamidosulphonyl ordi-(C₁₋₃-alkyl)-amidosulphonyl group, wherein an alkyl moiety may besubstituted in each case by a carboxy, aminocarbonyl,N-(C₁₋₃-alkyl)-aminocarbonyl or N,N-di-(C₁₋₃-alkyl)-aminocarbonyl groupor, in the 2 or 3 position, by a C₁₋₃-alkylamino ordi-(C₁₋₃-alkyl)-amino group,

[0025] by an amino, C₁₋₅-alkylamino, C₃₋₇-cycloalkylamino,phenyl-C₁₋₃-alkylamino, phenylamino, 6-membered heteroarylamino,amino-C₁₋₃-alkyl, N-(C₁₋₅-alkyl)-amino-C₁₋₃-alkyl,di-(C₁₋₅-alkyl)-amino-C₁₋₃-alkyl, C₃₋₇-cycloalkylamino-C₁₋₃-alkyl,N-(C₁₋₅-alkyl)-C₃₋₇-cycloalkylamino-C₁₋₃-alkyl, phenylamino-C₁₋₃-alkyl,N-(C₁₋₃-alkyl)-phenylamino-C₁₋₃-alkyl, phenyl-C₁₋₃-alkylamino-C₁₋₃-alkylor N-(C₁₋₅-alkyl)-phenyl-C₁₋₃-alkylamino-C₁₋₃-alkyl group or by a6-membered heteroarylamino-C₁₋₃-alkyl group optionally substituted atthe nitrogen atom by a C₁₋₅-alkyl group, while the N-alkyl moiety of theabovementioned groups may be substituted in each case by a cyano,carboxy, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl,2-[di-(C₁₋₃-alkyl)-amino]-ethylaminocarbonyl,3-[di-(C₁₋₃-alkyl)-amino]-propylaminocarbonyl,N-{2-[di-(C₁₋₃-alkyl)-amino]-ethyl}-N-(C₁₋₃-alkyl)-aminocarbonyl orN-{3-[di-(C₁₋₃-alkyl)-amino]-propyl}-N-(C₁₋₃-alkyl)-aminocarbonyl groupor in the 2 or 3 position by a hydroxy, C₁₋₃-alkoxy, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, pyrrolidino, piperidino,hexamethyleneimino, morpholino, piperazino or N-(C₁₋₃-alkyl)-piperazinogroup and the nitrogen atom of the abovementioned amino,N-(C₁₋₅-alkyl)-amino, C₃₋₇-cycloalkylamino, phenyl-C₁₋₃-alkylamino,phenylamino, 6-membered heteroarylamino, amino-C₁₋₃-alkyl- andN-(C₁₋₅-alkylamino)-C₁₋₃-alkyl groups may additionally be substituted

[0026] by a C₁₋₅-alkoxycarbonyl group,

[0027] by a formyl, trifluoroacetyl or benzoyl group,

[0028] by a carboxy-C₁₋₃-alkyl, aminocarbonyl-C₁₋₃-alkyl,N-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl orN,N-di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl group,

[0029] by a C₁₋₅-alkyl group which may be substituted, except in the 1position, by a hydroxy, C₁₋₃-alkoxy, amino, C₁₋₃-alkylamino ordi-(C₁₋₃-alkyl)-amino group,

[0030] by a C₂₋₄-alkanoyl group which may be substituted in the alkanoylmoiety by a carboxy, hydroxy, C₁₋₃-alkoxy, phenyl, amino, phthalimido,C₁₋₃-alkylamino,

[0031] di-(C₁₋₃-alkyl)-amino, pyrrolidino, piperidino,hexamethyleneimino or morpholino group or by a piperazino groupoptionally substituted at the nitrogen atom by a C₁₋₃-alkyl orphenyl-C₁₋₃-alkyl group, while the alkyl moiety of the abovementionedC₁₋₃-alkylamino- and di-(C₁₋₃-alkyl)-amino substituents may besubstituted in the 2 or 3 position by a hydroxy, C₁₋₃-alkoxy, amino,C₁₋₅-alkoxycarbonylamino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,phenyl, pyrrolidino, piperidino, hexamethyleneimino or morpholino group,

[0032] by a C₁₋₅-alkylsulphonyl group in which the alkyl moiety may besubstituted except in the 1 position by a di-(C₁₋₃-alkyl)-amino,pyrrolidino, piperidino, hexamethyleneimino or morpholino group,

[0033] by a phenyl-(C₁₋₃)-alkylsulphonyl or phenylsulphonyl groupoptionally substituted in the phenyl moiety by a fluorine, chlorine orbromine atom or by a C₁₋₃-alkyl or C₁₋₃-alkoxy group,

[0034] while additionally any carboxy, amino or imino group present maybe substituted by a group which can be cleaved in vivo.

[0035] By a group which can be cleaved in vivo from an imino or aminogroup is meant, for example, a hydroxy group, an acyl group such as thebenzoyl or pyridinoyl group or a C₁₋₁₆-alkanoyl group such as theformyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, anallyloxycarbonyl group, a C₁₋₁₆-alkoxycarbonyl group such as themethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl,octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl,undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, aphenyl-C₁₋₆-alkoxycarbonyl group such as the benzyloxycarbonyl,phenylethoxycarbonyl or phenylpropoxycarbonyl group, aC₁₋₃-alkylsulphonyl-C₂₋₄-alkoxycarbonyl,C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxycarbonyl orR_(a)CO—O—(R_(b)CR_(c))—O—CO group wherein

[0036] R_(a) denotes a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, phenyl orphenyl-C₁₋₃-alkyl group,

[0037] R_(b) denotes a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl orphenyl group and

[0038] R_(c) denotes a hydrogen atom, a C₁₋₃-alkyl orR_(a)CO—O—(R_(b)CR_(c))—O group wherein R_(a) to R_(c) are ashereinbefore defined,

[0039] and additionally for an amino group is meant the phthalimidogroup, while the abovementioned ester groups may also be used as a groupwhich can be converted into a carboxy group in vivo.

[0040] Also included are the compounds of general formula I of theGerman application no. 198 44 000.3 on which priority is based, in which

[0041] X denotes an oxygen or sulphur atom,

[0042] R₁ denotes a hydrogen atom or a C₁₋₃-alkyl group,

[0043] R₂ denotes a hydrogen, fluorine, chlorine, bromine or iodineatom, a C₁₋₃-alkyl or nitro group,

[0044] R₃ denotes a phenyl or naphthyl group, each of which may be monoor disubstituted by fluorine, chlorine or bromine atoms, by C₁₋₃-alkyl,C₁₋₃-alkoxy, cyano, trifluoromethyl, nitro, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, C₁₋₃-alkylsulphonylamino, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, C₂₋₄-alkanoyl-amino-C₁₋₃-alkyl,N-(C₂₋₄-alkanoyl)-C₁₋₃-alkylamino-C₁₋₃-alkyl ordi-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl groups, while the substituents may beidentical or different,

[0045] R₄ denotes a hydrogen atom or a C₁₋₃-alkyl group and

[0046] R₅ denotes a phenyl or naphthyl group optionally substituted by aC₁₋₃-alkyl group, each of which may additionally be substituted in thearomatic moiety

[0047] by a fluorine, chlorine, bromine or iodine atom, by a C₁₋₃-alkyl,C₁₋₃-alkoxy, cyano, nitro or trifluoromethyl group,

[0048] by a C₁₋₃-alkyl group optionally substituted by a C₁₋₃-alkyl,phenyl or phenyl-C₁₋₃-alkyl group piperidino, hexamethyleneimino,morpholino, piperazino group, while the abovementioned piperidino orhexamethyleneimino groups may additionally be substituted in the 3 or 4position by a hydroxy, C₁₋₃-alkoxy or carboxy group,

[0049] by a C₁₋₃-alkyl group optionally substituted by a hydroxy,C₁₋₃-alkoxy, carboxy or cyano group,

[0050] by a aminocarbonylamino, amidino or guanidino group optionallysubstituted by one or two C₁₋₃-alkyl groups,

[0051] by a piperidino, hexamethyleneimino, morpholino, piperazino orN-(C₁₋₃-alkyl)-piperazino group,

[0052] by a formyl, carboxy or trifluoroacetyl group,

[0053] by a carbonyl group which is substituted by a C₁₋₃-alkyl,C₁₋₃-alkoxy-C₁₋₃-alkyl, amino, C₁₋₅-alkylamino or di-(C₁₋₃-alkyl)-aminogroup, while the above-mentioned amino- and C₁₋₃-alkylamino groups mayadditionally be substituted at the nitrogen atom by acarboxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl ordi-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl group,

[0054] by a piperidinocarbonyl, hexamethyleneiminocarbonyl,morpholinocarbonyl, piperazinocarbonyl,N-(C₁₋₃-alkyl)-piperazinocarbonyl orN-(phenyl-C₁₋₃-alkyl)-piperazinocarbonyl group,

[0055] by an amino, C₁₋₅-alkylamino, amino-C₁₋₃-alkyl,N-(C₁₋₃-alkylamino)-C₁₋₃-alkyl or di-(C₁₋₅-alkylamino)-C₁₋₃-alkyl group,while the alkyl moiety of the above-mentioned C₁₋₃-alkylamino moietiesmay be substituted by a cyano, carboxy, aminocarbonyl,C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,2-[di-(C₁₋₃-alkyl)-amino]-ethylaminocarbonyl or3-[di-(C₁₋₃-alkyl)-amino]-propylaminocarbonyl group or in the 2 or 3position may be substituted by a hydroxy, C₁₋₃-alkoxy,di-(C₁₋₃-alkyl)-amino, piperidino, hexamethyleneimino, morpholino,piperazino or N-(C₁₋₃-alkyl)-piperazino group and the nitrogen atom ofthe abovementioned amino, C₁₋₃-alkylamino, amino-C₁₋₃-alkyl orN-(C₁₋₅-alkylamino)-C₁₋₃-alkyl moieties may additionally be substituted

[0056] by a C₁₋₅-alkoxycarbonyl group,

[0057] by a formyl or trifluoroacetyl group,

[0058] by a C₁₋₅-alkyl group which may be substituted, except in the 1position, by a hydroxy, C₁₋₃-alkoxy, amino, C₁₋₃-alkylamino ordi-(C₁₋₃)-alkylamino group,

[0059] by a C₂₋₄-alkanoyl group which may be substituted in the alkanoylmoiety by a carboxy, hydroxy, C₁₋₃-alkoxy, amino, C₂₋₄-alkanoylamino,C₁₋₅-alkoxycarbonylamino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,piperidino, hexamethyleneimino or morpholino group or by a piperazinogroup optionally substituted at the nitrogen atom by a C₁₋₃-alkyl orphenyl-C₁₋₃-alkyl group,

[0060] by a C₁₋₃-alkylsulphonyl, amidosulphonyl,C₁₋₃-alkylamidosulphonyl or di-(C₁₋₃-alkyl)-amidosulphonyl group,

[0061] by a phenyl-(C₁₋₃)-alkylsulphonyl or phenylsulphonyl groupoptionally substituted in the phenyl moiety by a fluorine, chlorine orbromine atom or by a C₁₋₃-alkyl or C₁₋₃-alkoxy group,

[0062] while additionally any carboxy, amino or imino group present maybe substituted by a group which can be cleaved in vivo,

[0063] the isomers and the salts thereof.

[0064] Preferred compounds of general formula I are those wherein

[0065] X denotes an oxygen or sulphur atom,

[0066] R₁ denotes a hydrogen atom, a C₁₋₃-alkyl, hydroxy,C₁₋₄-alkoxycarbonyl or C₂₋₄-alkanoyl group,

[0067] R₂ denotes a hydrogen, fluorine, chlorine, bromine or iodineatom, a C₁₋₃-alkyl or nitro group,

[0068] R₃ denotes a phenyl or naphthyl group, each of which may be mono-or disubstituted by fluorine, chlorine, bromine or iodine atoms, byC₁₋₃-alkyl, imidazolylmethyl, 2-carboxyethenyl,2-(C₁₋₃-alkoxycarbonyl)-ethenyl, C₁₋₃-alkoxy, cyano, carboxy,C₁₋₃-alkoxycarbonyl, trifluoromethyl, nitro, amino, phthalimidomethyl,2-carboxy-phenylcarbonylaminomethyl, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, C₁₋₃-alkylsulphonylamino, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, C₂₋₄-alkanoylamino-C₁₋₃-alkyl,N-(C₂₋₄-alkanoyl)-C₁₋₃-alkylamino-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, carboxy-C₁₋₃-alkylaminocarbonyl orC₁₋₃-alkoxycarbonyl-C₁₋₃-alkylaminocarbonyl groups, while thesubstituents may be identical or different,

[0069] R₄ denotes a hydrogen atom or a C₁₋₃-alkyl group and

[0070] R₅ denotes a phenyl or naphthyl group optionally substituted by aC₁₋₃-alkyl group, each of which may additionally be substituted in thearomatic moiety

[0071] by a fluorine, chlorine, bromine or iodine atom, by a C₁₋₃-alkyl,C₁₋₃-alkoxy, cyano, nitro or trifluoromethyl group, while theabovementioned alkyl group may simultaneously be substituted by acarboxy or C₁₋₃-alkoxycarbonyl group and an amino orC₁₋₄-alkoxycarbonylamino group,

[0072] a C₁₋₃-alkyl group which is substituted by a 4- to 7-memberedcycloalkyleneimino group, by a dehydropiperidino, morpholino,thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino,piperazino or N-(C₁₋₄-alkoxycarbonyl)-piperazino group, while theabovementioned piperidino, hexamethyleneimino, morpholino,thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino- andpiperazino groups may be substituted by a C₁₋₃-alkyl, phenyl orphenyl-C₁₋₃-alkyl group and the abovementioned piperidino groups mayadditionally be substituted by a C₁₋₃-alkyl group or in the 3 or 4position by a hydroxy, C₁₋₃-alkoxy, hydroxy-C₁₋₃-alkyl, carboxy,aminocarbonyl, N-(C₁₋₃-alkyl)-aminocarbonyl orN,N-di-(C₁₋₃-alkyl)-aminocarbonyl group,

[0073] by a C₁₋₃-alkyl group optionally substituted by a hydroxy,C₁₋₃-alkoxy, carboxy, C₁₋₃-alkoxycarbonyl or cyano group,

[0074] by an aminocarbonylamino, amidino or guanidino group optionallysubstituted by one or two C₁₋₃-alkyl groups,

[0075] by a piperidino, hexamethyleneimino, morpholino, piperazino orN-(C₁₋₃-alkyl)-piperazino group,

[0076] by a formyl, carboxy, C₁₋₃-alkoxycarbonyl or trifluoroacetylgroup,

[0077] by a carbonyl group which

[0078] is substituted by a C₁₋₃-alkyl, C₁₋₃-alkoxy-C₁₋₃-alkyl, amino,C₁₋₅-alkylamino or di-(C₁₋₃-alkyl)-amino group, while the abovementionedamino- and C₁₋₃-alkylamino groups may additionally be substituted at thenitrogen atom by a carboxy-C₁₋₃-alkyl or C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylgroup or by a C₂₋₃-alkyl group which may be substituted in the 2 or 3position by a hydroxy, C₁₋₃-alkoxy, amino, C₁₋₃-alkylamino ordi-(C₁₋₃-alkyl)-amino group,

[0079] by a pyrrolidinocarbonyl, pyrrolidinosulphonyl,piperidinocarbonyl, hexamethyleneiminocarbonyl, morpholinocarbonyl,piperazinocarbonyl, N-(C₁₋₃-alkyl)-piperazinocarbonyl orN-(phenyl-C₁₋₃-alkyl)-piperazinocarbonyl group,

[0080] by an amidosulphonyl, C₁₋₃-alkylamidosulphonyl ordi-(C₁₋₃-alkyl)-amidosulphonyl group, wherein an alkyl moiety may besubstituted by a carboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl,C₁₋₃-alkylaminocarbonyl or di-(C₁₋₃-alkyl)-aminocarbonyl group or in the2 or 3 position may be substituted by an amino, C₁₋₃-alkylamino ordi-(C₁₋₃-alkyl)-amino group,

[0081] by an amino, C₁₋₅-alkylamino, amino-C₁₋₃-alkyl,N-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, N-(2-hydroxyethyl)-amino-C₁₋₃-alkyl,N-(3-hydroxypropyl)-amino-C₁₋₃-alkyl, di-(C₁₋₅-alkyl)-amino-C₁₋₃-alkyl,N-(C₃₋₇-cycloalkyl)-amino-C₁₋₃-alkyl,N-(C₃₋₇-cycloalkyl)-N-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl orN-(phenyl-C₁₋₃-alkyl)-amino-C₁₋₃-alkyl group, while the N-alkyl moietyof the abovementioned groups may be substituted by a cyano, carboxy,C₁₋₃-alkylcarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl,2-[di-(C₁₋₃-alkyl)-amino]-ethylaminocarbonyl,3-[di-(C₁₋₃-alkyl)-amino]-propylaminocarbonyl,N-{2-[di-(C₁₋₃-alkyl)-amino]-ethyl}-N-(C₁₋₃-alkyl)-aminocarbonyl orN-{3-[di-(C₁₋₃-alkyl)-amino]-propyl}-N-(C₁₋₃-alkyl)-aminocarbonyl groupor may be substituted in the 2 or 3 position by a hydroxy, C₁₋₃-alkoxy,amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino or morpholino group, whilethe nitrogen atom of the abovementioned amino, C₁₋₅-alkylamino,amino-C₁₋₃-alkyl or N-(C₁₋₃-alkylamino)-C₁₋₃-alkyl moieties mayadditionally be substituted

[0082] by a C₁₋₅-alkoxycarbonyl group,

[0083] by a formyl, trifluoroacetyl or benzoyl group,

[0084] by a C₁₋₅-alkyl group which may be substituted, except in the 1position, by a hydroxy, C₁₋₃-alkoxy, amino, C₁₋₃-alkylamino ordi-(C₁₋₃)-alkylamino group,

[0085] by a C₂₋₄-alkanoyl group which may be substituted in the alkanoylmoiety by a hydroxy, C₁₋₃-alkoxy, amino, C₂₋₄-alkanoylamino,C₁₋₅-alkoxycarbonylamino, phthalimido, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, N-(C₁₋₃-alkyl)-phenylamino, pyrrolidino,piperidino or morpholino group or by a piperazino group optionallysubstituted at the nitrogen atom by a C₁₋₃-alkyl or phenyl-C₁₋₃-alkylgroup, while the N-alkyl moiety of the abovementioned groups may besubstituted in the 2 or 3 position by a methoxy, di-(C₁₋₃-alkyl)-aminoor morpholino group,

[0086] by a C₁₋₅-alkylsulphonyl group in which the alkyl moiety may besubstituted, except in the 1 position, by a di-(C₁₋₃-alkyl)-amino,pyrrolidino, piperidino, hexamethyleneimino or morpholino group,

[0087] by a pyridinyl or pyrimidinyl group,

[0088] by a phenyl, phenyl-(C₁₋₃)-alkylsulphonyl or phenylsulphonylgroup optionally substituted in the phenyl moiety by a C₁₋₃-alkyl group,

[0089] by a C₁₋₃-alkoxy group which is substituted by a carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group or is substituted in the 2 or 3position by an amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,N-(C₁₋₃-alkyl)-N-(phenyl-C₁₋₃-alkyl)-amino, piperidino orhexamethyleneimino group,

[0090] by a prop-1-enyl, 2-chloro-prop-1-enyl or prop-1-ynyl group whichis substituted in the 3 position by a di-(C₁₋₃-alkyl)-amino group,

[0091] the isomers and the salts thereof.

[0092] Particularly preferred compounds of general formula I are thosewherein

[0093] X denotes an oxygen atom,

[0094] R₁ denotes a hydrogen atom, a C₁₋₃-alkyl, C₁₋₄-alkoxycarbonyl orC₂₋₄-alkanoyl group,

[0095] R₂ denotes a hydrogen, fluorine, chlorine, bromine or iodineatom, a C₁₋₃-alkyl or nitro group,

[0096] R₃ denotes a phenyl group which may be mono- or disubstituted byfluorine, chlorine, bromine or iodine atoms, by C₁₋₃-alkyl,trifluoromethyl, imidazolylmethyl, 2-carboxyethenyl,2-C₁₋₃-alkoxycarbonyl-ethenyl, C₁₋₃-alkoxy, cyano, carboxy,C₁₋₃-alkoxycarbonyl, nitro, amino, phthalimidomethyl,2-carboxy-benzoylaminomethyl, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,C₁₋₃-alkylsulphonylamino, amino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,C₂₋₄-alkanoylamino-C₁₋₃-alkyl,N-(C₂₋₄-alkanoyl)-C₁₋₃-alkylamino-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, carboxy-C₁₋₃-alkylaminocarbonyl orC₁₋₃-alkoxycarbonyl-C₁₋₃-alkylaminocarbonyl groups, while thesubstituents may be identical or different,

[0097] R₄ denotes a hydrogen atom or a C₁₋₃-alkyl group and

[0098] R₅ denotes a phenyl or naphthyl group optionally substituted by aC₁₋₃-alkyl group, each of which may additionally be substituted in thearomatic moiety

[0099] by a fluorine, chlorine, bromine or iodine atom, by aC₁₋₃-alkoxy, cyano, nitro or trifluoromethyl group,

[0100] a C₁₋₃-alkyl group which is substituted by a 4- to 7-memberedcycloalkyleneimino group, by a dehydropiperidino, morpholino,thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino,piperazino or N-(C₁₋₄-alkoxycarbonyl)-piperazino group, while theabovementioned piperidino, hexamethyleneimino, morpholino and piperazinogroups may be substituted by a C₁₋₃-alkyl, phenyl or phenyl-C₁₋₃-alkylgroup and the abovementioned piperidino groups may additionally besubstituted by a C₁₋₃-alkyl group or may be substituted in the 3 or 4position by a hydroxy, C₁₋₃-alkoxy, hydroxy-C₁₋₃-alkyl, carboxy,aminocarbonyl, N-(C₁₋₃-alkyl)-aminocarbonyl orN,N-di-(C₁₋₃-alkyl)-aminocarbonyl group,

[0101] by a C₁₋₃-alkyl group optionally substituted by a hydroxy,C₁₋₃-alkoxy, carboxy, C₁₋₃-alkoxycarbonyl or cyano group,

[0102] by an aminocarbonylamino, amidino or guanidino group optionallysubstituted by one or two C₁₋₃-alkyl groups,

[0103] by a piperidino, hexamethyleneimino, morpholino, piperazino orN-(C₁₋₃-alkyl)-piperazino group,

[0104] by a formyl, carboxy, C₁₋₃-alkoxycarbonyl or trifluoroacetylgroup,

[0105] by a carbonyl group which

[0106] is substituted by a C₁₋₃-alkyl, C₁₋₃-alkoxy-C₁₋₃-alkyl, amino,C₁₋₅-alkylamino or di-(C₁₋₃-alkyl)-amino group, while the abovementionedamino and C₁₋₃-alkylamino groups may additionally be substituted at thenitrogen atom by a carboxy-C₁₋₃-alkyl, C₁₋₃-alkoxycarbonyl-C₁₋₃-alkyl orC₁₋₃-alkoxycarbonyl-C₁₋₃-alkyl group or by a C₂₋₃-alkyl group which maybe substituted in the 2 or 3 position by a hydroxy, C₁₋₃-alkoxy, amino,C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-amino group,

[0107] by a pyrrolidinocarbonyl, pyrrolidinosulphonyl,piperidinocarbonyl or hexamethyleneiminocarbonyl group,

[0108] by an amidosulphonyl, C₁₋₃-alkylamidosulphonyl ordi-(C₁₋₃-alkyl)-amidosulphonyl group, wherein an alkyl moiety may besubstituted by a carboxy, C₁₋₃-alkoxycarbonyl or dimethylaminocarbonylgroup or in the 2 or 3 position by a dimethylamino group,

[0109] by a straight-chain C₁₋₂-alkyl group which is terminallysubstituted by an amino, benzylamino, pyridylamino or pyrimidylaminogroup, by a C₁₋₄-alkylamino group in which the alkyl moiety may besubstituted in position 2, 3 or 4 by a hydroxy or methoxy group, or by aC₁₋₂-alkylamino group substituted in the C₁₋₂-alkyl moiety by a carboxy,C₁₋₃-alkoxycarbonyl or di-(C₁₋₃-alkyl)-aminocarbonyl group, while in theabovementioned groups any hydrogen atom present at the amino nitrogenatom may additionally be replaced

[0110] by a C₃₋₆-cycloalkyl group, by a C₁₋₄-alkyl group in which thealkyl moiety may be substituted in position 2, 3 or 4 by a hydroxygroup, by a C₁₋₂-alkylcarbonyl group optionally substituted by amethoxy, carboxy, C₁₋₃-alkoxycarbonyl, amino, methylamino,dimethylamino, acetylamino, C₁₋₅-alkoxycarbonylamino,N-methyl-C₁₋₅-alkoxycarbonylamino or morpholinocarbonylamino group, by aC₁₋₅-alkoxycarbonyl, C₁₋₄-alkylsulphonyl, phenylsulphonyl ortolylsulphonyl group,

[0111] by a 3-dimethylaminopropyl or 3-dimethylamino-prop-1-enyl group,

[0112] by an ethyl group which is substituted in the 1 position by anamino or C₁₋₅-alkoxycarbonylamino group,

[0113] by an ethyl group which is substituted in the 2 position by anamino or C₁₋₅-alkoxycarbonylamino group and by a carboxy orC₁₋₃-alkoxycarbonyl group,

[0114] by an amino or C₁₋₃-alkylamino group in which the alkyl moietymay be substituted by a cyano, carboxy, C₁₋₃-alkoxycarbonyl,aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl group or maybe substituted in the 2 or 3 position by an amino, methylamino,dimethylamino, acetylamino, N-methyl-acetylamino or morpholino group, byan N-(C₁₋₃-alkyl)-aminocarbonyl or N-(C₁₋₃-alkyl)-methylaminocarbonylgroup optionally substituted in the 2 or 3 position of the C₁₋₃-alkylmoiety by a dimethylamino group, while any hydrogen atom present at theamino nitrogen atom in the abovementioned groups may additionally bereplaced

[0115] by a formyl, trifluoroacetyl, benzoyl, C₁₋₄-alkoxycarbonyl orC₁₋₄-alkylaminocarbonyl group,

[0116] by a C₂₋₄-alkanoyl group which may be terminally substituted byan amino, acetylamino, C₁₋₄-alkoxycarbonylamino, pyrrolidino,piperidino, morpholino, piperazino, 4-methylpiperazino,4-benzylpiperazino or phthalimido group or by a C₁₋₃-alkylamino,N-acetyl-C₁₋₃-alkyl-amino or di-(C₁₋₃-alkyl)-amino group, while in theabovementioned C₁₋₃-alkylamino, N-acetyl-C₁₋₃-alkyl-amino- anddi-(C₁₋₃-alkyl)-amino groups any C₁₋₃-alkyl moiety may additionally besubstituted by a phenyl group or in the 2 or 3 position by a methoxy,dimethylamino or morpholino group,

[0117] by a C₁₋₄-alkylsulphonyl group in which the alkyl moiety mayadditionally be substituted in the 2 or 3 position by a dimethylamino,piperidino or morpholino group,

[0118] by a phenylsulphonyl or toluenesulphonyl group,

[0119] by a C₁₋₃-alkoxy group which is substituted by a carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, methylaminocarbonyl ordimethylaminocarbonyl group or is substituted in the 2 or 3 position byan amino, methylamino, dimethylamino, N-methyl-benzylamino, piperidinoor hexamethyleneimino group,

[0120] by a C₁₋₃-alkylaminocarbonyl or di-(C₁₋₃-alkyl)-aminocarbonylgroup wherein a C₁₋₃-alkyl moiety may be substituted in the 2 or 3position by a methoxy or dimethylamino group,

[0121] the isomers and the salts thereof.

[0122] Most particularly preferred compounds of general formula I arethose wherein

[0123] X denotes an oxygen atom

[0124] R₁ denotes a hydrogen atom,

[0125] R₂ denotes a hydrogen, chlorine or bromine atom, a methyl ornitro group,

[0126] R₃ denotes a phenyl group which may be substituted by a fluorine,chlorine or bromine atom, by a methyl, methoxy, aminomethyl,acetylaminomethyl, carboxy, methoxycarbonyl or imidazolylmethyl group,

[0127] R₄ denotes a hydrogen atom,

[0128] R₅ denotes a phenyl group which may be substituted

[0129] by a fluorine, chlorine or bromine atom, by a methyl, methoxy,nitro, cyano or trifluoromethyl group,

[0130] by a methyl or ethyl group, each of which is substituted by acarboxy, C₁₋₃-alkoxycarbonyl, cyano, azetidin-1-yl, pyrrolidino,piperidino, 4-phenylpiperidino, 3,6-dihydro-2H-pyridin-1-yl,hexamethyleneimino, morpholino, thiomorpholino, 1-oxido-thiomorpholino,piperazino, 4-methylpiperazino or 4-acetylpiperazino group, while theabovementioned piperidino groups may additionally be substituted by oneor two methyl groups or may be substituted in the 3 or 4 position by ahydroxy, methoxy, carboxy, hydroxymethyl, C₁₋₃-alkoxycarbonyl,aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl group,

[0131] by a straight-chain C₁₋₂-alkyl group which may be terminallysubstituted by an amino or benzylamino group, by a C₁₋₄-alkylamino groupin which the alkyl moiety in positions 2, 3 or 4 is substituted by ahydroxy or methoxy group, by a C₁₋₂-alkylamino group substituted in theC₁₋₂-alkyl moiety by a carboxy, C₁₋₃-alkoxycarbonyl ordimethylaminocarbonyl group, while in the abovementioned groups ahydrogen atom present at the amino nitrogen may additionally be replaced

[0132] by a C₃₋₆-cycloalkyl group, by a C₁₋₄-alkyl group in which thealkyl moiety may be substituted in positions 2, 3 or 4 by a hydroxygroup, or by a C₁₋₂-alkylcarbonyl group optionally substituted by anamino, methylamino or dimethylamino group,

[0133] by a 3-dimethylamino-prop-1-enyl group,

[0134] by an ethyl group which is substituted in the 1-position by anamino or C₁₋₄-alkoxycarbonylamino group,

[0135] by an amino or C₁₋₃-alkylamino group in which the alkyl moietymay be terminally substituted by a carboxy, aminocarbonyl,methylaminocarbonyl or dimethylaminocarbonyl group or in the 2 or 3position by an amino, methylamino, dimethylamino, acetylamino,N-acetyl-methylamino or morpholino group or by anN-(C₁₋₃-alkyl)-aminocarbonyl or N-(C₁₋₃-alkyl)-methylaminocarbonyl groupoptionally substituted in the 2 or 3 position by a dimethylamino group,while a hydrogen atom present at the amino nitrogen in theabovementioned groups may additionally be substituted

[0136] by a formyl or benzoyl group,

[0137] by a C₂₋₄-alkanoyl group which may be terminally substituted byan amino, acetylamino, pyrrolidino, piperidino, morpholino, piperazinoor 4-methylpiperazino group or by a C₁₋₃-alkylamino,N-acetyl-C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-amino group, while in theabovementioned C₁₋₃-alkylamino, N-acetyl-C₁₋₃-alkylamino ordi-(C₁₋₃-alkyl)-amino groups a C₁₋₃-alkyl moiety may additionally besubstituted in the 2 or 3 position by a methoxy, dimethylamino ormorpholino group,

[0138] by a C₁₋₄-alkylsulphonyl group which may be substituted in the 2or 3 position by a dimethylamino group,

[0139] by a pyrrolidinosulphonyl group, an aminosulphonyl,C₁₋₃-alkylaminosulphonyl or di-(C₁₋₃-alkyl)-aminosulphonyl group,wherein in each case a C₁₋₃-alkyl moiety may be substituted by acarboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl, methylaminocarbonyl ordimethylaminocarbonyl group or, except in the 1 position, by adimethylamino group,

[0140] by a C₂₋₃-alkoxy group which is substituted in the 2 or 3position by a dimethylamino or piperidino group,

[0141] by an aminocarbonyl, C₁₋₃-alkylaminocarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group, wherein in each case the C₁₋₃-alkylmoieties may be substituted by a methoxy or dimethylamino group, exceptin the 1 positions,

[0142] particularly those compounds of the above general formula Iwherein

[0143] X and R₂ to R₄ are as hereinbefore defined,

[0144] R₁ denotes a hydrogen atom and

[0145] R₅ denotes a phenyl group which may be substituted

[0146] by a methyl or ethyl group, each of which is substituted by anazetidin-1-yl, pyrrolidino, piperidino, hexamethyleneimino, morpholino,1-oxido-thiomorpholino, piperazino, 4-methylpiperazino or4-acetylpiperazino group, while the abovementioned piperidino groups mayadditionally be substituted by one or two methyl groups or in the 4position may be substituted by a hydroxy, methoxy, hydroxymethyl,aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl group,

[0147] by a straight-chain C₁₋₂-alkyl group which is terminallysubstituted by an amino group or by a C₁₋₃-alkylamino group, while thealkyl moiety of the C₁₋₃-alkylamino group may be substituted inpositions 2 or 3 by a hydroxy or methoxy group and in the abovementionedgroups the hydrogen atom present at the amino nitrogen may additionallybe replaced

[0148] by a C₃₋₆-cycloalkyl group, by a C₁₋₃-alkyl group in which thealkyl moiety in positions 2 or 3 may be substituted by a hydroxy group,or by a C₁₋₂-alkylcarbonyl group substituted by an amino, methylamino ordimethylamino group,

[0149] by an ethyl group substituted in the 1 position by an aminogroup,

[0150] by an amino or C₁₋₃-alkylamino group in which the alkyl moietymay be terminally substituted by a carboxy, aminocarbonyl,methylaminocarbonyl, dimethylaminocarbonyl,N-(2-dimethylamino-ethyl)-aminocarbonyl orN-(2-dimethylamino-ethyl)-N-methyl-aminocarbonyl group or may besubstituted in the 2 or 3 position by an amino, methylamino,dimethylamino, acetylamino, N-acetyl-methylamino or morpholino group,while the hydrogen atom present at the amino nitrogen of theabovementioned groups may additionally be replaced

[0151] by a C₂₋₄-alkanoyl group which may be terminally substituted byan amino, acetylamino, pyrrolidino, piperidino, morpholino, piperazinoor 4-methylpiperazino group or by a C₁₋₃-alkylamino,N-acetyl-C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-amino group, while in theabovementioned C₁₋₃-alkylamino, N-acetyl-C₁₋₃-alkylamino ordi-(C₁₋₃-alkyl)-amino groups a C₁₋₃-alkyl moiety may additionally besubstituted in the 2 or 3 position by a methoxy, dimethylamino ormorpholino group,

[0152] by a C₁₋₄-alkylsulphonyl group which may be substituted in the 2or 3 position by a dimethylamino group,

[0153] by a pyrrolidinosulphonyl group, an aminosulphonyl,C₁₋₃-alkylaminosulphonyl or di-(C₁₋₃-alkyl)-aminosulphonyl group,wherein in each case a C₁₋₃-alkyl moiety may be substituted by acarboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl ordimethylaminocarbonyl group or, except in the 1 position, by adimethylamino group,

[0154] by a C₁₋₃-alkoxy group substituted in the 2 or 3 position by adimethylamino or piperidino group,

[0155] by an aminocarbonyl, C₁₋₃-alkylaminocarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group, wherein in each case a C₁₋₃-alkylmoiety may be substituted by a methoxy or dimethylamino group, except inthe 1 position,

[0156] the isomers and the salts thereof.

[0157] The following are mentioned as examples of particularly preferredcompounds of general formula I:

[0158] (a)(Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone,

[0159] (b)(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone,

[0160] (c)(Z)-3-{1-[4-(2-morpholinoethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone,

[0161] (d)(Z)-3-{1-[4-(2-dimethylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinoneand

[0162] (e)(Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[0163] and the salts thereof.

[0164] According to the invention, the new compounds may be obtained,for example, by the following methods known in principle from theliterature:

[0165] a. Reaction of a Compound of General Formula

[0166] wherein

[0167] X, R₂ and R₃ are as hereinbefore defined,

[0168] R₆ denotes a hydrogen atom, a protecting group for the nitrogenatom of the lactam group or a bond to a solid phase and

[0169] Z₁ denotes a halogen atom, a hydroxy, alkoxy or aralkoxy group,e.g. a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group,

[0170] with an amine of general formula

[0171] wherein

[0172] R₄ and R₅ are as hereinbefore defined,

[0173] and if necessary subsequently cleaving any protecting group usedfor the nitrogen atom of the lactam group or cleaving from a solidphase.

[0174] A protecting group for the nitrogen atom of the lactam groupmight be for example an acetyl, benzoyl, ethoxycarbonyl,tert.butyloxycarbonyl or benzyloxycarbonyl group and

[0175] the solid phase might be a Rink resin such as a p-benzyloxybenzylalcohol resin, whilst the bond may conveniently be formed via anintermediate member such as a 2,5-dimethoxy-4-hydroxy-benzyl derivative.

[0176] The reaction is conveniently carried out in a solvent such asdimethylformamide, toluene, acetonitrile, tetrahydrofuran,dimethylsulphoxide, methylene chloride or mixtures thereof, optionallyin the presence of an inert base such as triethylamine,N-ethyl-diisopropylamine or sodium hydrogen carbonate at temperaturesbetween 20 and 175° C., whilst any protecting group used can be cleavedsimultaneously by transamidation.

[0177] If Z₁ in a compound of general formula II denotes a halogen atom,the reaction is preferably carried out in the presence of an inert baseat temperatures between 20 and 120° C.

[0178] If Z₁ in a compound of general formula II denotes a hydroxy,alkoxy or aralkoxy group, the reaction is preferably carried out attemperatures between 20 and 200° C.

[0179] If any protecting group used subsequently has to be cleaved, thisis conveniently carried out either hydrolytically in an aqueous oralcoholic solvent, e.g. in methanol/water, ethanol/water,isopropanol/water, tetrahydrofuran/water, dioxane/water,dimethylformamide/water, methanol or ethanol in the presence of analkali metal base such as lithium hydroxide, sodium hydroxide orpotassium hydroxide at temperatures between 0 and 100° C., preferably attemperatures between 10 and 50° C.,

[0180] or advantageously by transamidation with a primary or secondaryorganic base such as methylamine, butylamine, dimethylamine orpiperidine in a solvent such as methanol, ethanol, dimethylformamide andmixtures thereof or in an excess of the amine used at temperaturesbetween 0 and 100° C., preferably at temperatures between 10 and 50° C.

[0181] Any solid phase used is preferably cleaved using trifluoroaceticacid and water in the presence of a dialkylsulphide such asdimethylsulphide at temperatures between 0 and 35° C., preferably atambient temperature.

[0182] b. In order to prepare a compound of general formula I whichcontains an aminomethyl group and wherein X denotes an oxygen atom:

[0183] Reduction of a Compound of General Formula

[0184] wherein

[0185] R₁ to R₄ are as hereinbefore defined and

[0186] R₇ has the meanings given for R₅ hereinbefore, with the provisothat that R₅ contains a cyano group.

[0187] The reduction is preferably carried out by catalytichydrogenation with hydrogen in the presence of a catalyst such aspalladium/charcoal or platinum in a solvent such as methanol, ethanol,ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacialacetic acid, optionally with the addition of an acid such ashydrochloric acid at temperatures between 0 and 50° C., but preferablyat ambient temperature, and at a hydrogen pressure of 1 to 7 bar, butpreferably 3 to 5 bar.

[0188] c. In order to prepare a compound of general formula I wherein R₁denotes a hydrogen atom and X denotes an oxygen atom:

[0189] Reduction of a Compound of General Formula

[0190] wherein

[0191] R₂ to R₅ are as hereinbefore defined.

[0192] The reduction is preferably carried out by catalytichydrogenation with hydrogen in the presence of a catalyst such aspalladium/charcoal or platinum in a solvent such as methanol, ethanol,ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacialacetic acid, at temperatures between 0 and 50° C., but preferably atambient temperature, and at a hydrogen pressure of 1 to 7 bar, butpreferably 3 to 5 bar.

[0193] If according to the invention a compound of general formula I isobtained which contains an alkoxycarbonyl group, this can be convertedby hydrolysis into a corresponding carboxy compound, or

[0194] if a compound of general formula I is obtained which contains anamino or alkylamino group, this may be converted by alkylation orreductive alkylation into a corresponding alkylamino or dialkylaminocompound, or

[0195] if a compound of general formula I is obtained which contains anamino or alkylamino group, this may be converted by acylation into acorresponding acyl compound, or

[0196] if a compound of general formula I is obtained which contains acarboxy group, this may be converted by esterification or amidation intoa corresponding ester or aminocarbonyl compound, or

[0197] if a compound of general formula I is obtained wherein R₃ denotesa phenyl group which contains a chlorine, bromine or iodine atom, thismay be converted into a corresponding alkenylated compound by reactionwith an alkenyl compound, or

[0198] if a compound of general formula I is obtained wherein R₃ denotesa phenyl group which contains a chlorine, bromine or iodine atom, thismay be converted into a corresponding alkynylated compound by reactionwith an alkynyl compound.

[0199] The subsequent hydrolysis is preferably carried out in an aqueoussolvent, e.g. in water, isopropanol/water, tetrahydrofuran/water ordioxane/water, in the presence of an acid such as trifluoroacetic acid,hydrochloric acid or sulphuric acid or in the presence of an alkalimetal base such as lithium hydroxide, sodium hydroxide or potassiumhydroxide at temperatures between 0 and 100° C., preferably attemperatures between 10 and 50° C.

[0200] The subsequent reductive alkylation is preferably carried out ina suitable solvent such as methanol, methanol/water,methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane ordimethylformamide optionally with the addition of an acid such ashydrochloric acid in the presence of catalytically activated hydrogen,e.g. hydrogen in the presence of Raney nickel, platinum orpalladium/charcoal, or in the presence of a metal hydride such as sodiumborohydride, sodium cyanoborohydride, lithium borohydride or lithiumaluminium hydride at temperatures between 0 and 100° C., preferably attemperatures between 20 and 80° C.

[0201] The subsequent alkylation is carried out with an alkylating agentsuch as an alkyl halide or dialkyl sulphate such as methyl iodide,dimethylsulphate or propyl bromide preferably in a solvent such asmethanol, ethanol, methylene chloride, tetrahydrofuran, toluene,dioxane, dimethylsulphoxide or dimethylformamide optionally in thepresence of an inorganic or a tertiary organic base such astriethylamine, N-ethyl-diisopropylamine or dimethylaminopyridine,preferably at temperatures between 20° C. and the boiling temperature ofthe solvent used.

[0202] The subsequent acylation is preferably carried out in a solventsuch as methylene chloride, diethyl ether, tetrahydrofuran, toluene,dioxane, acetonitrile, dimethylsulphoxide or dimethylformamide,optionally in the presence of an inorganic or a tertiary organic base,preferably at temperatures between 20° C. and the boiling temperature ofthe solvent used. The acylation with a corresponding acid is preferablycarried out in the presence of a dehydrating agent, e.g. in the presenceof isobutyl chloroformate, tetraethyl orthocarbonate, trimethylorthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionylchloride, trimethylchlorosilane, phosphorus trichloride, phosphoruspentoxide, N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexyl-carbodiimide/N-hydroxysuccinimide,N,N′-dicyclohexylcarbodiimide/1-hydroxy-benztriazole,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole,N,N′-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, andoptionally with the addition of a base such as pyridine,4-dimethylamino-pyridine, N-methyl-morpholine or triethylamine,conveniently at temperatures between 0 and 150° C., preferably attemperatures between 0 and 100° C., and the acylation with acorresponding reactive compound such as an anhydride, ester, imidazolideor halide thereof is optionally carried out in the presence of atertiary organic base such as triethylamine, N-ethyl-diisopropylamine orN-methylmorpholine at temperatures between 0 and 150° C., preferably attemperatures between 50 and 100° C.

[0203] The subsequent esterification or amidation is expediently carriedout by reacting a corresponding reactive carboxylic acid derivative witha corresponding alcohol or amine as described hereinbefore.

[0204] The subsequent alkenylation is preferably carried out in asolvent such as dimethylformamide, dimethylacetamide or acetonitrile inthe presence of a palladium catalyst such asbis-(triphenylphosphine)-palladium-dichloride and preferably in thepresence of a suitable base such as, for example, triethylamine,tributylamine, N-ethyl-diisopropylamine or sodium acetate attemperatures between 20 and 120° C. (cf. R. F. Heck, Org. Reactions 27,345-390 (1982).

[0205] The subsequent alkynylation is preferably carried out in asolvent such as benzene, toluene, dimethylformamide or chloroform in thepresence of a palladium catalyst such astetrakis-triphenylphosphine-palladium and copper-(I)-iodide, preferablyin the presence of a suitable base such as triethylamine, attemperatures between 20 and 100° C. (cf. also N. A. Bumagin et al.Synthesis 1984, 728-729; K. Sonogashira et al. Tetrahedron Lett. 1975,4467).

[0206] Alkenyl-substituted arylamines are prepared under the conditionsof palladium-catalysed coupling. To do this, aryl halide and the alkenylcompound are reacted with a catalytic amount of a palladium catalystsuch as bis-(triphenylphosphine)-palladium-dichloride in a solvent suchas DMF, dimethylacetamide or acetonitrile in the presence of an inertbase such as, for example, triethylamine, tributylamine,N-ethyl-diisopropylamine or sodium acetate at temperatures between 20and 120° C.

[0207] In the reactions described hereinbefore, any reactive groupspresent such as carboxy, amino, alkylamino or imino groups may beprotected during the reaction by conventional protecting groups whichare cleaved again after the reaction.

[0208] For example, a protecting group for a carboxyl group may be atrimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranylgroup and

[0209] a protecting group for an amino, alkylamino or imino group may bean acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl,tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or2,4-dimethoxybenzyl group and additionally, for the amino group, aphthalyl group.

[0210] Any protecting group used is optionally subsequently cleaved forexample by hydrolysis in an aqueous solvent, e.g. in water,isopropanol/water, tetrahydrofuran/water or dioxane/water, in thepresence of a acid such as trifluoroacetic acid, hydrochloric acid orsulphuric acid or in the presence of an alkali metal base such aslithium hydroxide, sodium hydroxide or potassium hydroxide, attemperatures between 0 and 100° C., preferably at temperatures between10 and 50° C.

[0211] However, a benzyl, methoxybenzyl or benzyloxycarbonyl group iscleaved, for example, hydrogenolytically, e.g. with hydrogen in thepresence of a catalyst such as palladium/charcoal in a solvent such asmethanol, ethanol, ethyl acetate, dimethylformamide,dimethylformamide/acetone or glacial acetic acid, optionally with theaddition of an acid such as hydrochloric acid or glacial acetic acid attemperatures between 0 and 50° C., but preferably at ambienttemperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3to 5 bar.

[0212] A methoxybenzyl group may also be cleaved in the presence of anoxidising agent such as cerium(IV)ammonium nitrate in a solvent such asmethylene chloride, acetonitrile or acetonitrile/water at temperaturesof between 0 and 50° C., but preferably at ambient temperature.

[0213] A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisole.

[0214] A tert.butyl or tert.butyloxycarbonyl group is preferably cleavedby treating with an acid such as trifluoroacetic acid or hydrochloricacid, optionally using a solvent such as methylene chloride, dioxan,ethyl acetate or ether.

[0215] A phthalyl group is preferably cleaved in the presence ofhydrazine or a primary amine such as methylamine, ethylamine orn-butylamine in a solvent such as methanol, ethanol, isopropanol,toluene/water or dioxan at temperatures between 20 and 50° C.

[0216] Moreover, chiral compounds of general formula I obtained may beresolved into their enantiomers and/or diastereomers.

[0217] Thus, for example, the compounds of general formula I obtainedwhich occur as racemates may be separated by methods known per se (cf.Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6,Wiley Interscience, 1971) into their optical antipodes and compounds ofgeneral formula I with at least 2 asymmetric carbon atoms may beresolved into their diastereomers on the basis of theirphysical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

[0218] The enantiomers are preferably separated by column separation onchiral phases or by recrystallisation from an optically active solventor by reacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid,dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, N-acetylglutamic acid,aspartic acid, N-acetylaspartic acid or quinic acid. An optically activealcohol may be for example (+)- or (−)-menthol and an optically activeacyl group in amides, for example, may be a (+)- or(−)-menthyloxycarbonyl group.

[0219] Furthermore, the compounds of formula I obtained may be convertedinto the salts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts with inorganic or organic acids. Acidswhich may be used for this purpose include for example hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid,succinic acid, lactic acid, citric acid, tartaric acid, maleic acid ormethanesulphonic acid.

[0220] Moreover, if the new compounds of formula I thus obtained containa carboxy group, they may subsequently, if desired, be converted intothe salts thereof with inorganic or organic bases, particularly forpharmaceutical use into the physiologically acceptable salts thereof.Suitable bases for this purpose include for example sodium hydroxide,potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine andtriethanolamine.

[0221] The compounds of general formulae I to VIII used as startingmaterials are known from the literature in some cases or may be obtainedby methods known from the literature or are described in the Examples.

[0222] As already mentioned, the new compounds of general formula Iwherein R₁ denotes a hydrogen atom or a prodrug group have valuablepharmacological properties, particularly inhibitory effects on variouskinases, especially on complexes of CDK's (CDK1, CDK2, CDK3, CDK4, CDK5,CDK6, CDK7, CDK8 and CDK9) with their specific cyclins (A, B1, B2, C,D1, D2, D3, E, F, G1, G2, H, I and K), on viral cyclin (cf. L. Mengtaoin J. Virology 71(3), 1984-1991 (1997)) and on receptor-tyrosine kinasessuch as HER2, EGFR, FGFR, IGF-1 R and KDR, on the proliferation ofcultivated human tumour cells and after oral administration on thegrowth of tumours in nude mice which have been infected with humantumour cells.

[0223] The biological properties of the compounds listed in Table 1 weretested as follows:

[0224] Test 1

[0225] Inhibition of Cyclin/CDK Enzyme, In Vitro Activity

[0226] High Five™ insect cells (BTI-TN-5B1-4) which had been infectedwith a high titre of recombinant baculovirus were used to produce activehuman cyclin/CDK holoenzymes. By using a baculovirus vector whichcontained two promoters (polyhedrin enhancer promoter, P10 enhancerpromoter), GST-tagged cyclins (e.g. cyclin D1 or cyclin D3) with thecorresponding His₆-tagged CDK subunit (e.g. for CDK4 or CDK6) wereexpressed in the same cell. The active holoenzyme was isolated byaffinity chromatography on glutathione sepharose. Recombinant GST-taggedpRB (aa 379-928) was produced in E. coli and purified by affinitychromatography on glutathione sepharose.

[0227] The substrates used for the kinase assays depended on thespecific kinases. Histone H1 (Sigma) was used as the substrate forcyclin E/CDK2, cyclin A/CDK2, cyclin B/CDK1 and for v-cyclin/CDK6.GST-tagged pRB (aa 379-928) was used as substrate for cyclin D1/CDK4,cyclin D3/CDK4, cyclin D1/CDK6 and for cyclin D3/CDK6.

[0228] Lysates of the insect cells infected with recombinant baculovirusor recombinant kinases (obtained from the lysates by purification) wereincubated together with radiolabelled ATP in the presence of a suitablesubstrate with various concentrations of the inhibitor in a 1% DMSOsolution (dimethyl sulphoxide) for 45 minutes at 30° C. The substrateproteins with associated radioactivity were precipitated with 5% TCA(trichloroacetic acid) in water-repellent PVDF multi-well microtitreplates (Millipore) or with 0.5% phosphoric acid solution on Whatman P81filters. After the addition of scintillation liquid the radioactivitywas measured in a Wallace 1450 Microbeta Liquid Scintillation Counter.For each concentration of the substance double measurements were carriedout; IC₅₀ values were calculated for the enzyme inhibition.

[0229] Test 2

[0230] Inhibition of the Proliferation of Cultivated Human Tumour Cells

[0231] Cells of the Leimyosarcoma tumour cell line SK-UT-1B (obtainedfrom the American Type Culture Collection (ATCC)) were cultivated inMinimum Essential Medium with non-essential amino acids (Gibco),supplemented with sodium pyruvate (1 mmol), glutamine (2 mmol) and 10%foetal calf serum (Gibco) and harvested during the log-growth phase.Then the SK-UT-1B cells were added to Cytostar® multi-well plates(Amersham) at a density of 4000 cells per well and incubated overnightin an incubator. Various concentrations of the compounds (dissolved inDMSO; final concentration: <1%) were added to the cells. After 48 hours'incubation ¹⁴C-thymidine (Amersham) was added to each well andincubation was continued for a further 24 hours. The quantity of¹⁴C-thymidine incorporated into the tumour cells in the presence of theinhibitor and representing the number of cells in the S phase wasmeasured in a Wallace 1450 Microbeta Liquid Scintillation Counter. IC₅₀values for the inhibition of proliferation (=inhibition of incorporated¹⁴C-thymidine) were calculated, correcting for the background radiation.All the measurements were done twice.

[0232] Test 3

[0233] In Vivo Effects on Tumour-Bearing Nude Mice

[0234] 10⁶ cells [SK-UT-1B, or non-small cell lung tumour NCI-H460(obtained from ATCC)] in a volume of 0.1 ml were injected subcutaneouslyinto male and/or female nude mice (NMRI nu/nu; 25-35 g; N=10-20);alternatively, small fragments of SK-UT-1 B or NCI-H460 cell clumps wereimplanted subcutaneously. One to three weeks after the injection orimplantation a kinase inhibitor was administered daily by oral route fora period of 2 to 4 weeks (by oesophageal tube). The size of the tumourwas measured three times a week using a digital sliding gauge. Theeffect of a kinase inhibitor on the tumour growth was determined as apercentage inhibition compared with a control group treated withplacebo.

[0235] The Table which follows contains the results obtained in in vitrotest 2: Inhibition of SKUT-1B- Compound (Example proliferation no.) IC₅₀[μM] 117 0.34 170 0.22 133 0.48 134 0.56 188 0.15

[0236] In view of their biological properties, the new compounds ofgeneral formula I, their isomers and physiologically acceptable saltsare suitable for the treatment of diseases characterised by excessive orabnormal cell proliferation.

[0237] Such diseases include (with no claim to completeness): viralinfections (e.g. HIV and Kaposi's sarcoma); inflammation and autoimmunediseases (e.g. colitis, arthritis, Alzheimer's disease,glomerulonephritis and wound healing); bacterial, fungal and/orparasitic infections; leukaemias, lymphoma and solid tumours; skindiseases (e.g. psoriasis); bone diseases; cardiovascular diseases (e.g.restenosis and hypertrophy). They are also useful for protectingproliferating cells (e.g. hair, intestinal, blood and progenitor cells)against DNA damage caused by radiation, UV treatment and/or cytostatictreatment.

[0238] The new compounds may be used for the short-term or long-termtreatment of the abovementioned diseases, optionally in conjunction withother ‘state of the art’ compounds such as other cytostatics.

[0239] The dosage required to achieve such an effect is appropriately0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg by intravenous route, and0.1 to 100 mg/kg, preferably 0.3 to 30 mg/kg by oral route, in each caseadministered 1 to 4 times a day. For this purpose, the compounds offormula I prepared according to the invention may be formulated,optionally together with other active substances, with one or more inertconventional carriers and/or diluents, e.g. with corn starch, lactose,glucose, microcrystalline cellulose, magnesium stearate,polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substancessuch as hard fat or suitable mixtures thereof, to produce conventionalgalenic preparations such as plain or coated tablets, capsules, powders,suspensions or suppositories.

[0240] The Examples which follow are intended to illustrate theinvention:

[0241] Abbreviations Used:

[0242] CDI=N,N′-carbonyldiimidazole

[0243] DMF=dimethylformamide

[0244] HOBt=1-hydroxy-1H-benzotriazole

[0245] TBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-bis(tetramethylene)-uroniumhexafluorophosphate

[0246] THF=Tetrahydrofuran

EXAMPLE 1

[0247] (Z)-3-(1-Anilino-1-phenyl-methylidene)-2-indolinone

[0248] a) 1-acetyl-2-indolinone

[0249] 13.3 g (0.1 mol) of 2-indolinone and 30 ml of acetic anhydrideare stirred for 3 hours at 170° C. After cooling, 150 ml of ice waterare added, the crystalline product is suction filtered, washed withwater and dried.

[0250] Yield: 16.6 g (95% of theory),

[0251] Melting point: 129-130° C.

[0252] b) 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone

[0253] 35.0 g (0.2 mol) of 1-acetyl-2-indolinone are dissolved in 300 mlof acetic anhydride and after the addition of 135 g (0.6 mol) oftriethyl orthobenzoate the mixture is refluxed for 22 hours. The solventis distilled off and the residue diluted with petroleum ether. After 18hours' standing at ambient temperature, the crystalline precipitate issuction filtered, washed and dried.

[0254] Yield: 41.2 g (67% of theory).

[0255] c) (Z)-3-(1-Anilino-1-phenyl-methylidene)-2-indolinone

[0256] 450 mg (1.5 mmol) of1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 0.41 ml of(4.5 mmol) of aniline are stirred in 7 ml of DMF for 90 minutes at 120°C. After cooling to ambient temperature 7 ml of methanol and 3 ml of 1Nsodium hydroxide solution are added. The mixture is stirred for 20minutes, then diluted with water, the crystalline reaction product issuction filtered and dried.

[0257] Yield: 49% of theory,

[0258] Melting point: 325° C.

[0259] C₂₁H₁₆N₂O (312.37)

[0260] Mass spectrum: M⁺=312

EXAMPLE 2

[0261](Z)-3-[1-(4-methoxy-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0262] a) 1-acetyl-3-(1-hydroxy-1-phenyl-methylidene)-2-indolinone

[0263] 880 mg (5 mmol) of 1-acetyl-2-indolinone and 610 mg (5 mmol) ofbenzoic acid are dissolved in 15 ml of DMF and after the addition of 1.8g (5.5 mmol) of TBTU, 840 mg (5.5 mmol) of HOBt and 3.2 g (25 mmol) ofN-ethyl-N,N-diisopropyl-amine are stirred for 16 hours at ambienttemperature. The solution is stirred into dilute hydrochloric acid, theprecipitate is suction filtered and dried at 60° C.

[0264] Yield: 1.1 g (80% of theory),

[0265] Melting point: 126-129° C.

[0266] b) 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone

[0267] 5.6 g (20 mmol) of1-acetyl-3-(1-hydroxy-1-phenyl-methylidene)-2-indolinone are suspendedin 45 ml of toluene and while cooling with ice combined with 4.2 g (20mmol) of phosphorus pentachloride and then stirred for 18 hours atambient temperature. The precipitate formed after cooling with ice issuction filtered and dried.

[0268] Yield. 5.3 g (89% of theory).

[0269] c)(Z)-3-[1-(4-methoxy-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0270] 0.18 g (1.5 mmol) of 4-methoxyaniline and 0.2 g (0.28 mmol) oftriethylamine are dissolved in 5 ml of dichloromethane and at 5° C.combined with a solution of 0.45 g (1.5 mmol) of1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone in 10 ml ofdichloromethane and then stirred for 3 hours at ambient temperature.After removal of the solvent in vacuo the residue is taken up in ethylacetate/water. The organic phase is washed with water, dried and thesolvent is eliminated in vacuo. Then the mixture is dissolved in 15 mlof methanol, combined with 3 ml of 1N sodium hydroxide solution, stirredfor 3 hours at ambient temperature and diluted with water and ethylacetate. The organic phase is dried and concentrated by evaporation. Theresidue is heated in ethyl acetate, cooled, then suction filtered anddried.

[0271] Yield: 100 mg (20% of theory),

[0272] Melting point: 267-270° C.

[0273] C₂₂H₁₈N₂O₂ (342.40)

[0274] Mass spectrum: M⁺=342

[0275] Calc.: C, 77.17; H, 5.30; N, 8.18. Found: 76.43; 5.39; 8.06.

EXAMPLE 3

[0276](Z)-3-[1-(3-methoxy-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0277] Prepared analogously to Example 2 from1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and3-methoxyaniline in THF and subsequent treatment with sodium hydroxidesolution.

[0278] Yield: 69% of theory,

[0279] Melting point: 218-221° C.

[0280] C₂₂H₁₈N₂O₂ (342.40)

[0281] Mass spectrum: M⁺=342

[0282] Calc.: C, 77.17; H, 5.30; N, 8.18. Found: 76.74; 5.30; 7.74.

EXAMPLE 4

[0283](Z)-3-[1-(2-methoxy-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0284] Prepared analogously to Example 1 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and2-methoxyaniline in DMF and subsequent treatment with sodium hydroxidesolution in methanol.

[0285] Yield: 44% of theory,

[0286] Melting point: 237° C.

[0287] C₂₂H₁₈N₂O₂ (342.40)

[0288] Mass spectrum: M⁺=342

[0289] R_(f) value: 0.47 (silica gel; petroleum ether/ethyl acetate=4:6)

[0290] C₂₂H₁₈N₂O₂ x H₂O (360.42)

[0291] Calc.: C, 73.32; H, 5.59; N, 7.77. Found: 73.51; 5.61; 7.66.

EXAMPLE 5

[0292](Z)-3-[1-(3-methoxymethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0293] Prepared analogously to Example 2 from1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and3-methoxymethyl-aniline-hydrochloride in THF and subsequent treatmentwith sodium hydroxide solution in methanol.

[0294] Yield: 28% of theory,

[0295] Melting point: 182-184° C.

[0296] C₂₃H₂₀N₂O₂ (356.43)

[0297] Mass spectrum: M⁺=356

[0298] Calc.: C, 77.51; H, 5.66; N, 7.86. Found: 77.12; 5.91; 7.74.

EXAMPLE 6

[0299](Z)-3-[1-(3-methyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0300] Prepared analogously to Example 2 from1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and m-toluidinein dichloromethane and subsequent treatment with sodium hydroxidesolution in methanol.

[0301] Yield: 3% of theory,

[0302] Melting point: 218-220° C.

[0303] C₂₂H₁₈N₂O (326.40)

[0304] Mass spectrum: M⁺=326

EXAMPLE 7

[0305](Z)-3-[1-(2-methoxycarbonyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0306] Prepared analogously to Example 1 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and methylanthranilate in DMF and subsequent brief treatment with sodium hydroxidesolution in methanol.

[0307] Yield: 12% of theory,

[0308] Melting point: 241-244° C.

[0309] C₂₃H₁₈N₂O₃ (370.41)

[0310] Mass spectrum: M⁺=370

[0311] Calc.: C, 74.58; H, 4.90; N, 7.56. Found: 73.87; 4.85; 7.44.

EXAMPLE 8

[0312](Z)-3-[1-(2-carboxy-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0313] 176 mg (0.48 mmol) of(Z)-3-[1-(2-methoxycarbonyl-phenylamino)-1-phenyl-methylidene]-2-indolinoneare dissolved in 15 ml of methanol and 2 ml of dioxane and after theaddition of 1.4 ml of 1N sodium hydroxide solution stirred for two hoursat 80° C. Then the mixture is neutralised 1.4 ml of 1N hydrochloric acidwhile being cooled, the product precipitated is suction filtered, washedwith water and dried.

[0314] Yield: 100 mg (59% of theory),

[0315] Melting point: 227-230° C.

[0316] C₂₂H₁₆N₂O₃ (356.38)

[0317] Mass spectrum: M⁺=356

[0318] R_(f) value: 0.30 (silica gel; dichloromethane/methanol/glacialacetic acid=19:1:0.1)

EXAMPLE 9

[0319](Z)-3-[1-(3-carboxy-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0320] a) 1-benzoyl-3-(1-hydroxy-1-phenyl-methylidene)-2-indolinone

[0321] 26.6 g (0.2 mol) of 2-indolinone and 53.8 g (0.44 mol) of4-dimethylamino-pyridine are dissolved in 400 ml of DMF and after theaddition of 30.9 g (0.22 mol) of benzoylchloride in 100 ml of DMFstirred for 45 minutes at 45° C. The solution is poured onto 3 l ofwater and 100 ml of conc. hydrochloric acid, the precipitate formed issuction filtered, recrystallised from glacial acetic acid and dried.

[0322] Yield: 11.8 g (17% of theory),

[0323] Melting point: 185-187° C.

[0324] b) 1-benzoyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone

[0325] Prepared analogously to Example 2b from1-benzoyl-3-(1-hydroxy-1-phenyl-methylidene)-2-indolinone and phosphoruspentachloride in toluene.

[0326] Yield: 99% of theory,

[0327] Melting point: 170-176° C.

[0328] c)(Z)-3-[1-(3-carboxy-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0329] Prepared analogously to Example 2c from1-benzoyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and ethyl3-aminobenzoate and subsequent total saponification with sodiumhydroxide solution in methanol.

[0330] Yield: 60% of theory,

[0331] C₂₂H₁₆N₂O₃ (356.38)

[0332] Mass spectrum: M⁺=356

[0333] R_(f) value: 0.33 (silica gel; petroleum ether/ethyl acetate=3:2)

EXAMPLE 10

[0334](Z)-3-{1-[3-(aminocarbonyl)phenylamino]-1-phenyl-methylidene}-2-indolinone

[0335] Prepared analogously to Example 9 from1-benzoyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and3-aminobenzoic acid amide in THF and subsequent treatment with sodiumhydroxide solution in methanol.

[0336] Yield: 76% of theory,

[0337] Melting point: 258-263° C.

[0338] C₂₂H₁₇N₃O₂ (355.40)

[0339] Mass spectrum: M⁺=355

EXAMPLE 11

[0340](Z)-3-[1-(3-ethoxycarbonylmethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0341] a) 3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone

[0342] 6.15 g (20 mmol) of1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone are suspended ina little ethanol. 10 ml of 4N sodium hydroxide solution are added andthe mixture is stirred for 1.5 hours at ambient temperature. After theaddition of 100 ml of water the precipitate is suction filtered, washedwith water and a little ether and dried at 80° C.

[0343] Yield 2.8 g (56% of theory),

[0344] Melting point: 168-169° C.

[0345] b)(Z)-3-[1-(3-ethoxycarbonylmethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0346] Prepared analogously to Example 1c from3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and ethyl3-aminophenylacetate in DMF.

[0347] Yield: 71% of theory,

[0348] Melting point: 178-181° C.

[0349] C₂₅H₂₂N₂O₃ (398.47)

[0350] Mass spectrum: M⁺=398

[0351] R_(f) value: 0.52 (silica gel; dichloromethane/methanol=24:1)

[0352] Calc.: C, 75.36; H, 5.56; N, 7.03. Found: 75.23; 5.69; 6.95.

EXAMPLE 12

[0353](Z)-3-[1-(3-carboxymethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0354] Prepared analogously to Example 8 by saponification of(Z)-3-[1-(3-ethoxycarbonylmethyl-phenylamino)-1-phenyl-methylidene]-2-indolinonein sodium hydroxide solution.

[0355] Yield: 90% of theory,

[0356] Melting point: 268-270° C.

[0357] C₂₃H₁₈N₂O₃ (370.41)

[0358] Mass spectrum: M⁺=370

[0359] R_(f) value: 0.21 (silica gel; dichloromethane/methanol=19:1)

[0360] Calc.: C, 74.58; H, 4.90; N, 7.56. Found: 74.54; 4.94; 7.59.

EXAMPLE 13

[0361](Z)-3-[1-(4-ethoxycarbonyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0362] Prepared analogously to Example 2 from1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and ethyl4-aminobenzoate in dichloromethane and subsequent treatment with sodiumhydroxide solution in methanol.

[0363] Yield: 19% of theory,

[0364] Melting point: 227-228° C.

[0365] C₂₄H₂₀N₂O₃ (384.44)

[0366] Mass spectrum: M⁺=384

[0367] Calc.: C, 74.98; H, 5.24; N, 7.29. Found: 74.37; 5.08; 7.02.

EXAMPLE 14

[0368](Z)-3-[1-(3-ethoxycarbonyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0369] Prepared analogously to Example 9c and 8 from1-benzoyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and ethyl3-aminobenzoate in THF and subsequent treatment with sodium hydroxidesolution in methanol.

[0370] Yield: 45% of theory,

[0371] Melting point: 194-195° C.

[0372] C₂₄H₂₀N₂O₃ (384.44)

[0373] Mass spectrum: M⁺=384

[0374] Calc.: C, 74.98; H, 5.24; N, 7.29. Found: 74.01; 5.28; 6.96.

EXAMPLE 15

[0375](Z)-3-[1-(4-ethoxycarbonylmethyl-phenylamino)-1-phenyl-me-thylidene]-2-indolinone

[0376] Prepared analogously to Example 1 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and ethyl4-aminophenylacetate in DMF and subsequent treatment with piperidine.

[0377] Yield: 64% of theory,

[0378] Melting point: 167-168° C.

[0379] C₂₅H₂₂N₂O₃ (398.47)

[0380] Mass spectrum: M⁺=398

[0381] Calc.: C, 75.36; H, 5.56; N, 7.03. Found: 75.41; 5.63; 7.10.

EXAMPLE 16

[0382](Z)-3-[1-(4-carboxymethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0383] Prepared analogously to Example 8 from(Z)-3-[1-(4-ethoxycarbonylmethyl-phenylamino)-1-phenyl-methylidene]-2-indolinoneand sodium hydroxide solution in ethanol.

[0384] Yield: 81% of theory,

[0385] Melting point: 214-216° C.

[0386] C₂₃H₁₈N₂O₃ (370.41)

[0387] Mass spectrum: M⁺=370

[0388] Calc.: C, 74.58; H, 4.90; N, 7.56. Found: 74.82; 4.78; 7.74.

EXAMPLE 17

[0389](Z)-3-[1-(4-carboxy-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0390] Prepared analogously to Example 8 from(Z)-3-[1-(4-ethoxycarbonyl-phenylamino]-1-phenyl-methylidene]-2-indolinoneand sodium hydroxide solution in ethanol.

[0391] Yield: 96% of theory,

[0392] Melting point: 312-316° C.

[0393] C₂₂H₁₆N₂O₃ (356.38)

[0394] Mass spectrum: M⁺=356

[0395] Calc.: C, 74.15; H, 4.53; N, 7.86. Found: 73.23; 4.48; 7.61.

EXAMPLE 18

[0396](Z)-3-[1-(4-dimethylaminocarbonyl-phenylamino)-1-phenyl-me-thylidene]-2-indolinone

[0397] 285 mg (0.8 mmol) of(Z)-3-[1-(4-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone and330 mg (4 mmol) of dimethylamine-hydrochloride are dissolved in 8 ml ofDMF and after the addition of 385 mg (1.2 mmol) of TBTU, 184 mg (1.2mmol) of HOBt and 1.03 g (8 mmol) of N-ethyl-N,N-diisopropylamine, themixture is stirred for 14 hours at ambient temperature. The solution isdiluted with water, the product precipitated is suction filtered, washedwith water and ethanol and dried.

[0398] Yield: 270 mg (88% of theory),

[0399] Melting point: 240-243° C.

[0400] C₂₄H₂₁N₃O₂ (383.45)

[0401] Mass spectrum: M⁺=383

[0402] Calc.: C, 75.18; H, 5.52; N, 10.96. Found: 75.19; 5.60; 10.94.

EXAMPLE 19

[0403](Z)-3-[1-(4-methylaminocarbonyl-phenylamino)-1-phenyl-me-thylidene]-2-indolinone

[0404] Prepared analogously to Example 18 from(Z)-3-[1-(4-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone,methylamine-hydrochloride, TBTU, HOBt and N-ethyl-N,N-diisopropylaminein DMF.

[0405] Yield: 68% of theory,

[0406] Melting point: 290-293° C.

[0407] C₂₃H₁₉N₃O₂ (369.43)

[0408] Mass spectrum: M⁺=369

[0409] Calc.: C, 74.78; H, 5.19; N, 11.37. Found: 75.58; 5.19; 11.22.

EXAMPLE 20

[0410](Z)-3-[1-(4-aminocarbonyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0411] 356 mg (1 mmol) of(Z)-3-[1-(4-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone aredissolved in 10 ml of DMF and combined with 194 mg (1 mmol) of CDI. Themixture is stirred for 2 hours at ambient temperature, 2 ml ofmethanolic ammonia solution are added, then stirring is continued for 16hours at ambient temperature. Then water is added, the precipitate isremoved by suction filtering, washed with water and a little ether anddried at 80° C.

[0412] Yield: 270 mg (76% of theory),

[0413] Melting point: 321-323° C.

[0414] C₂₂H₁₇N₃O₂ (355.40)

[0415] Mass spectrum: M⁺=355

[0416] Calc.: C, 74.35; H, 4.82; N, 11.82. Found: 74.04; 4.93; 11.27.

EXAMPLE 21

[0417](Z)-3-[1-(3-methylaminocarbonyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0418] Prepared analogously to Example 18 from(Z)-3-[1-(3-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone,methylamine-hydrochloride, TBTU, HOBt and triethylamine in DMF.

[0419] Yield: 41% of theory,

[0420] Melting point: 250-252° C.

[0421] C₂₃H₁₉N₃O₂ (369.43)

[0422] Mass spectrum: M⁺=369

EXAMPLE 22

[0423](Z)-3-[1-(3-dimethylaminocarbonyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0424] Prepared analogously to Example 21 from(Z)-3-[1-(3-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone,dimethylamine-hydrochloride, TBTU, HOBt and triethylamine in DMF.

[0425] Yield: 87% of theory,

[0426] Melting point: 261-263° C.

[0427] C₂₄H₂₁N₃O₂ (383.45)

[0428] Mass spectrum: M⁺=383

[0429] R_(f) value: 0.51 (silica gel; ethyl acetate)

[0430] Calc.: C, 75.18; H, 5.52; N, 10.96. Found: 75.05; 5.58; 10.93.

EXAMPLE 23

[0431](Z)-3-[1-(3-ethoxycarbonylmethylaminocarbonyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0432] Prepared analogously to Example 21 from(Z)-3-[1-(3-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone,glycine ethyl ester, TBTU, HOBt and triethylamine in DMF.

[0433] Yield: 91% of theory,

[0434] Melting point: 233-235° C.

[0435] C₂₆H₂₃N₃O₄ (441.49)

[0436] Mass spectrum: M⁺=441

[0437] R_(f) value: 0.55 (silica gel; ethyl acetate)

[0438] Calc.: C, 70.73; H, 5.25; N, 9.52. Found: 70.69; 5.33; 9.52.

EXAMPLE 24

[0439](Z)-3-[1-(3-carboxymetylaminocarbonyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0440] Prepared analogously to Example 8 from(Z)-3-[1-(3-ethoxycarbonylmethylaminocarbonyl-phenylamino)-1-phenyl-methylidene]-2-indolinoneand sodium hydroxide solution in ethanol.

[0441] Yield: 81% of theory,

[0442] Melting point: 248-250° C.

[0443] C₂₄H₁₉N₃O₄ (413.44)

[0444] Mass spectrum: (M−H)⁻=412

EXAMPLE 25

[0445](Z)-3-{1-[3-(N-ethoxycarbonylmethyl-N-methyl-aminocarbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[0446] Prepared analogously to Example 21 from(Z)-3-[1-(3-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone,sarcosine ethyl ester, TBTU, HOBt and triethylamine in DMF.

[0447] Yield: 91% of theory,

[0448] Melting point: 148-150° C.

[0449] C₂₇H₂₅N₃O₄ (455.52)

[0450] Mass spectrum: M⁺=455

[0451] Calc.: C, 71.19; H, 5.53; N, 9.22. Found: 70.75; 5.63; 9.38.

EXAMPLE 26

[0452](Z)-3-{1-[3-(N-carboxymethyl-N-methyl-aminocarbonyl)-phenyl-amino]-1-phenyl-methylidene}-2-indolinone

[0453] Prepared analogously to Example 8 from(Z)-3-{1-[3-(N-ethoxycarbonylmethyl-N-methylaminocarbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinoneand sodium hydroxide solution in ethanol.

[0454] Yield: 89% of theory,

[0455] Melting point: 218-220° C.

[0456] C₂₅H₂₁N₃O₄ (427.46)

[0457] Mass spectrum: (M−H)⁻=426

EXAMPLE 27

[0458](Z)-3-{1-[(3-(2-dimethylaminoethyl-aminocarbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[0459] Prepared analogously to Example 21 from(Z)-3-[1-(3-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone,N,N-dimethylethylene-diamine, TBTU, HOBt and triethylamine in DMF.

[0460] Yield: 66% of theory,

[0461] Melting point: 203-205° C.

[0462] C₂₆H₂₆N₄O₂ (426.52)

[0463] Mass spectrum: M⁺=426

[0464] R_(f) value: 0.17 (silica gel; ethyl acetate/methanol=6:4)

[0465] Calc.: C, 73.22; H, 6.14; N, 13.14. Found: 72.42; 6.29; 12.85.

EXAMPLE 28

[0466](Z)-3-[1-(4-tert.butoxycarbonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0467] Prepared analogously to Example 1 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-tert.butoxycarbonylamino-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[0468] Yield: 64% of theory,

[0469] Melting point: 244-246° C.

[0470] C₂₆H₂₅N₃O₃ (427.51)

[0471] Mass spectrum: M⁺=427

[0472] Calc.: C, 73.05; H, 5.86; N, 9.83. Found: 72.80; 5.84; 9.92.

EXAMPLE 29

[0473](Z)-3-[1-(4-formylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0474] a)(Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone

[0475] 1.7 g (4 mmol) of(Z)-3-[1-(4-tert.butoxycarbonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinoneare suspended in 15 ml of dichloromethane and after the addition of 35ml of ethyl acetate/hydrogen chloride for 18 hours at ambienttemperature and stirred for 2 hours at 40° C. After cooling the mixtureis diluted with ether and the precipitate is suction filtered. Theresidue is divided between sodium chloride solution and methylenechloride, the organic extracts are dried and concentrated byevaporation.

[0476] Yield: 1.0 g (77% of theory,

[0477] Melting point: 299-300° C.

[0478] b)(Z)-3-[1-(4-formylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0479] 200 mg (0.6 mmol) of(Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone and 5ml of ethyl formate are stirred in 2.5 ml of DMF for 60 hours at 90° C.After removal of the solvent in vacuo ethyl acetate is added and themixture is again concentrated by evaporation. The residue is stirredwith ether, suction filtered and dried.

[0480] Yield: 73% of theory.

[0481] Melting point: 268-269° C.

[0482] C₂₂H₁₇N₃O₂ (355.40)

[0483] Mass spectrum: M⁺=355

EXAMPLE 30

[0484](Z)-3-[1-(3-formylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0485] Prepared analogously to Example 29 from(Z)-3-[1-(3-aminophenylamino)-1-phenyl-methylidene]-2-indolinone andethyl formate in DMF.

[0486] Yield: 80% of theory,

[0487] Melting point: 231° C.

[0488] C₂₂H₁₇N₃O₂ (355.40)

[0489] Mass spectrum: M⁺=355

[0490] C₂₂H₁₇N₃O₂ x H₂O (373.41)

[0491] Calc.: C, 70.76; H, 5.13; N, 11.25. Found: 70.66; 4.77; 11.03.

EXAMPLE 31

[0492](Z)-3-[1-(4-acetylamino-phenylamino]-1-phenyl-methylidene]-2-indolinone196 mg (0.6 mmol) of(Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone aredissolved in 5 ml of glacial acetic acid and after the addition of 0.1 g(1 mmol) of acetic anhydride stirred for 3 hours at ambient temperature.Then 15 ml of water are added, the product precipitated is suctionfiltered, washed with water and dried.

[0493] Yield: 210 mg (95% of theory),

[0494] Melting point: 236-238° C.

[0495] C₂₃H₁₉N₃O₂ (369.43)

[0496] Mass spectrum: M⁺=369

[0497] Calc.: C, 74.78; H, 5.18; N, 11.37. Found: 74.32; 5.28; 11.15.

EXAMPLE 32

[0498](Z)-3-[1-(3-acetylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0499] Prepared analogously to Example 31 from(Z)-3-[1-(3-aminophenylamino)-1-phenyl-methylidene]-2-indolinone andacetic anhydride in glacial acetic acid.

[0500] Yield: 89% of theory,

[0501] Melting point: 285-288° C.

[0502] C₂₃H₁₉N₃O₂ (369.43)

[0503] Mass spectrum: M⁺=369

[0504] Calc.: C, 74.78; H, 5.18; N, 11.37. Found: 74.53; 5.37; 11.37.

EXAMPLE 33

[0505](Z)-3-[1-(3-trifluoroacetylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0506] Prepared analogously to Example 31 from(Z)-3-[1-(3-aminophenylamino)-1-phenyl-methylidene]-2-indolinone andtrifluoroacetic anhydride in trifluoroacetic acid.

[0507] Yield: 79% of theory,

[0508] Melting point: 273-276° C.

[0509] C₂₃H₁₆F₃N₃O₂ (423.40)

[0510] Mass spectrum: M⁺=423

[0511] Calc.: C, 65.25; H, 3.81; N, 9.92. Found: 65.48; 3.85; 9.96.

EXAMPLE 34

[0512](Z)-3-[1-(4-tert.butoxycarbonylaminomethylcarbonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0513] Prepared analogously to Example 18 from(Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone,N-tert.butoxycarbonyl-glycine, TBTU, HOBt and N-methylmorpholine in DMF.

[0514] Yield: 31% of theory,

[0515] Melting point: 243-244° C. (decomposition)

[0516] C₂₈H₂₈N₄O₄ (484.56)

[0517] Mass spectrum: M⁺=484

[0518] Calc.: C, 69.41; H, 5.82; N, 11.56. Found: 68.52; 5.73; 11.30.

EXAMPLE 35

[0519](Z)-3-[1-(4-aminomethylcarbonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone-hydrochloride

[0520] Prepared analogously to Example 29a from(Z)-3-[1-(4-tert.butoxycarbonylaminomethylcarbonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinoneand ethyl acetate/hydrogen chloride in dichloromethane.

[0521] Yield: 73% of theory,

[0522] Melting point: 289-290° C.

[0523] C₂₃H₂₀N₄O₂ (384.44)

[0524] Mass spectrum: M⁺=384

[0525] C₂₃H₂₀N₄O₂ x HCl x H₂O

EXAMPLE 36

[0526](Z)-3-{1-[3-(N-trifluoroacetyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[0527] 636 mg (1.5 mmol) of(Z)-3-[1-(3-trifluoroacetylamino-phenylamino)-1-phenyl-methylidene]-2-indolinoneare dissolved in 20 ml of acetone and after the addition of 423 mg (3mmol) of potassium carbonate and 0.25 g (3 mmol) of methyl iodidestirred for 18 hours at ambient temperature. The reaction solution isfreed from the solvent in vacuo after the insoluble matter has beenfiltered off. The residue is divided between dichloromethane/water, theorganic phase is dried and concentrated by evaporation. The residue istriturated with ether, suction filtered and dried.

[0528] Yield: 550 mg (85% of theory),

[0529] Melting point: 224-227° C.

[0530] C₂₄H₁₈F₃N₃O₂ (437.43)

[0531] Mass spectrum: M⁺=437

[0532] Calc.: C, 65.90; H, 4.15; N, 9.61. Found: 65.96; 4.22; 9.59.

EXAMPLE 37

[0533](Z)-3-[1-(3-methylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0534] Prepared analogously to Example 8 from(Z)-3-{1-[3-(N-trifluoroacetyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinoneand sodium hydroxide solution in methanol.

[0535] Yield: 91% of theory,

[0536] Melting point: 247-248° C.

[0537] C₂₂H₁₉N₃O (341.42)

[0538] Mass spectrum: M⁺=341

[0539] Calc.: C, 77.40; H, 5.61; N, 12.31. Found: 76.65; 5.60; 12.09.

EXAMPLE 38

[0540](Z)-3-{1-[3-(N-acetyl-N-methylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[0541] Prepared analogously to Example 31 from(Z)-3-[1-(3-methylamino-phenylamino)-1-phenyl-methylidene]-2-indolinoneand acetic anhydride in glacial acetic acid.

[0542] Yield: 73% of theory,

[0543] Melting point: 237-239° C.

[0544] C₂₄H₂₁N₃O₂ (383.45)

[0545] Mass spectrum: M⁺=383

[0546] Calc.: C, 75.18; H, 5.52; N, 10.96. Found: 74.51; 5.51; 10.80.

EXAMPLE 39

[0547](Z)-3-[1-(4-propionylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0548] a) 3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone

[0549] 4.0 g (13.2 mmol) of1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone are suspended in50 ml of ethanol and after the addition of 10 ml of 4N sodium hydroxidesolution stirred for 90 minutes at ambient temperature. The solution isdiluted with 150 ml of water, the crystalline product is suctionfiltered, washed and dried.

[0550] Yield: 2.8 g (80% of theory),

[0551] Melting point: 168-169° C.

[0552] b) N-propionyl-4-nitroaniline

[0553] 6.9 g (50 mmol) of nitroaniline are suspended in 50 ml ofpropionic acid and combined with 9.1 g (50 mmol) of propionic acidanhydride. The mixture is heated for 90 minutes to 50° C. and thenstirred for 16 hours at ambient temperature. Then 200 ml of water areadded. The precipitate is suction filtered, washed and dried.

[0554] Yield: 9.4 g (97% of theory),

[0555] Melting point: 192-195° C.

[0556] c) 4-propionylamino-aniline

[0557] 250 mg (2 mmol) of N-propionyl-4-nitroaniline are dissolved in200 ml of methanol and combined with 0.6 g of 10% palladium/charcoal.The product is hydrogenated in a hydrogen atmosphere at 2 bar for 30minutes. Then the catalyst is filtered off and the solvent is eliminatedin vacuo.

[0558] Yield: 4.5 g (91% of theory),

[0559] Melting point: 82-84° C.

[0560] C₉H₁₂N₂O (164.21)

[0561] Calc.: C, 65.83; H, 7.37; N, 17.06. Found: 65.99; 7.36; 17.02.

[0562] c)(Z)-3-[1-(4-propionylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0563] 265 mg (1 mmol) of 3-(1-ethoxy-1-phenyl-methylidene)-2-indolinoneare dissolved in 5 ml of DMF and after the addition of 300 mg (1.8 mmol)of 4-propionylamino-aniline stirred for 8 hours at 150° C. Aftercooling, it is diluted with water, the crystalline product is suctionfiltered, washed and dried.

[0564] Yield: 280 mg (68% of theory),

[0565] Melting point: 255-256° C.

[0566] C₂₄H₂₁N₃O₂ (383.45)

[0567] Mass spectrum: M⁺=383

[0568] C₂₄H₂₁N₃O₂ x H₂O (401.47)

[0569] Calc.: C, 71.80; H, 5.77; N, 10.47. Found: 71.62; 5.61; 10.50.

EXAMPLE 40

[0570](Z)-3-[1-(4-methoxymethylcarbonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0571] Prepared analogously to Examples 1 and 39 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-methoxymethylcarbonylamino-aniline in DMF and subsequent treatmentwith sodium hydroxide solution in methanol.

[0572] Yield: 80% of theory,

[0573] Melting point: 238-240° C.

[0574] C₂₄H₂₁N₃O₃ (399.45)

[0575] Mass spectrum: M⁺=399

[0576] Calc.: C, 72.17; H, 5.30; N, 10.52. Found: 71.92; 5.33; 10.44.

EXAMPLE 41

[0577](Z)-3-[1-(4-dimethylaminomethylcarbonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0578] Prepared analogously to Example 1 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-dimethylaminomethyl-carbonylamino-aniline in DMF and subsequenttreatment with sodium hydroxide solution in methanol.

[0579] Yield: 68% of theory,

[0580] Melting point: 234-236° C.

[0581] C₂₅H₂₄N₄O₂ (412.50)

[0582] Mass spectrum: M⁺=412

[0583] R_(f) value: 0.28 (silica gel; ethyl acetate/methanol=19:1)

[0584] Calc.: C, 72.29; H, 5.86; N, 13.58. Found: 72.35; 5.83; 13.37.

EXAMPLE 42

[0585](Z)-3-[1-(4-Diethylaminomethylcarbonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone-hydrochloride

[0586] Prepared analogously to Example 1 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-diethylaminomethyl-carbonylamino-aniline in DMF and subsequenttreatment with sodium hydroxide solution in methanol.

[0587] Yield: 80% of theory,

[0588] Melting point: 267-269° C.

[0589] C₂₇H₂₈N₄O₂ (440.55)

[0590] Mass spectrum: M⁺=440

[0591] R_(f) value: 0.32 (silica gel; dichloromethane/methanol=19:1)

[0592] C₂₇H₂₈N₄O₂ x HCl x 1.5H₂O (504.03)

[0593] Calc.: C, 64.34; H, 6.40; N, 11.12. Found: 64.72; 6.69; 11.16.

EXAMPLE 43

[0594](Z)-3-[1-(4-morpholinomethylcarbonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0595] a) N-morpholinomethylcarbonyl-4-nitroaniline

[0596] 2.6 g (30 mmol) of morpholine and 4.2 g (30 mmol) of potassiumcarbonate are suspended in 120 ml of acetone. 5.3 g (20 mmol) ofN-bromoacetyl-4-nitro-aniline, dissolved in 80 ml of acetone, are addeddropwise over a period of 20 minutes and then stirred for 2 hours atambient temperature. The precipitate is filtered off and the solvent iseliminated in vacuo. The residue is suspended with water. Theprecipitate is suction filtered and dried in a drying cupboard.

[0597] Yield: 5.0 g (94% of theory),

[0598] Melting point: 148-149° C.

[0599] b) 4-morpholinomethylcarbonylamino-aniline

[0600] Prepared analogously to Example 39c by catalytic hydrogenationfrom N-morpholinomethylcarbonyl-4-nitroaniline.

[0601] Yield: 92% of theory,

[0602] Melting point: 106-107° C.

[0603] C₁₂H₁₇N₃O₂ (235.29)

[0604] Calc.: C, 61.26; H, 7.28; N, 17.86. Found: 60.91; 7.28; 17.60.

[0605] c)(Z)-3-[1-(4-morpholinomethylcarbonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0606] Prepared analogously to Example 1 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-morpholinomethyl-carbonylamino-aniline in DMF and subsequent treatmentwith sodium hydroxide solution in methanol.

[0607] Yield: 97% of theory,

[0608] Melting point: 246-248° C.

[0609] C₂₇H₂₆N₄O₃ (454.53)

[0610] Mass spectrum: M⁺=454

[0611] R_(f) value: 0.35 (silica gel; ethyl acetate)

[0612] C₂₇H₂₆N₄O₃ x 0.5H₂O (463.54)

[0613] Calc.: C, 69.96; H, 5.87; N, 12.09. Found: 70.36; 5.90; 12.08.

EXAMPLE 44

[0614](Z)-3-{1-[4-(4-methylpiperazinomethylcarbonylamino-phenylamino]-1-phenyl-methylidene}-2-indolinone

[0615] Prepared analogously to Example 43 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-(4-methyl-piperazinomethylcarbonylamino)-aniline in DMF and subsequenttreatment with sodium hydroxide solution in methanol.

[0616] Yield: 86% of theory,

[0617] Melting point: 282-284° C.

[0618] C₂₈H₂₉N₅O₂ (467.58)

[0619] Mass spectrum: M⁺=467

[0620] R_(f) value: 0.32 (silica gel; dichloromethane/methanol=9:1)

[0621] C₂₈H₂₉N₅O₂ x 0.5H₂O (476.58)

[0622] Calc.: C, 70.57; H, 6.34; N, 14.70. Found: 70.88; 6.29; 14.54.

EXAMPLE 45

[0623](Z)-3-[1-(4-ethylaminocarbonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0624] 196 mg (0.6 mmol) of(Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone aresuspended in 10 ml of THF and after the addition of 70 mg (0.1 mmol) ofethyl isocyanate stirred for 140 hours at ambient temperature. Theproduct precipitated is suction filtered, washed with ether and dried.

[0625] Yield: 200 mg (84% of theory),

[0626] Melting point: 264-265° C.

[0627] C₂₄H₂₂N₄O₂ (398.47)

[0628] Mass spectrum: M⁺=398

[0629] Calc.: C, 72.34; H, 5.57; N, 14.06. Found: 71.70; 5.83; 13.49.

EXAMPLE 46

[0630](Z)-3-[1-(4-butylaminocarbonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0631] Prepared analogously to Example 45 from(Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone andbutyl isocyanate in THF.

[0632] Yield: 72% of theory,

[0633] Melting point: 216-217° C.

[0634] C₂₆H₂₆N₄O₂ (426.52)

[0635] Mass spectrum: M⁺=426

[0636] Calc.: C, 73.22; H, 6.14; N, 13.14. Found: 72.74; 5.94; 12.67.

EXAMPLE 47

[0637](Z)-3-{1-[4-(N-acetyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[0638] Prepared analogously to Example 1 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-(N-acetyl-N-methyl-amino)-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[0639] Yield: 50% of theory,

[0640] Melting point: 287-288° C.

[0641] C₂₄H₂₁N₃O₂ (383.45)

[0642] Mass spectrum: M⁺=383

[0643] Calc.: C, 75.18; H, 5.52; N, 10.96. Found: 75.18; 5.62; 10.89.

EXAMPLE 48

[0644](Z)-3-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone-hydrochloride

[0645] Prepared analogously to Example 43 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-aniline in DMF andsubsequent treatment with sodium hydroxide solution in methanol.

[0646] Yield: 30% of theory,

[0647] Melting point: 290-292° C.

[0648] C₂₆H₂₆N₄O₂ (426.52)

[0649] Mass spectrum: M⁺=426

[0650] C₂₆H₂₆N₄O₂ x HCl x 2H₂O (499.00)

[0651] Calc.: C, 62.58; H, 6.26; N, 11.23; Cl, 7.10. Found: 62.68; 6.07;11.19; 7.88.

EXAMPLE 49

[0652](Z)-3-{1-[4-(N-Diethylaminomethylcarbonyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[0653] Prepared analogously to Example 43 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-(N-diethylaminomethylcarbonyl-N-methyl-amino)-aniline in DMF andsubsequent treatment with sodium hydroxide solution in methanol.

[0654] Yield: 64% of theory,

[0655] Melting point: 242-247° C.

[0656] C₂₈H₃₀N₄O₂ (454.58)

[0657] Mass spectrum: M⁺=454

[0658] R_(f) value: 0.56 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[0659] C₂₈H₃₀N₄O₂ x 0.5H₂O (454.57)

[0660] Calc.: C, 72.55; H, 6.74; N, 12.09. Found: 72.70; 6.41; 12.11.

EXAMPLE 50

[0661](Z)-3-{1-[4-(N-piperidinomethylcarbonyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[0662] Prepared analogously to Example 43 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-(N-piperidinomethylcarbonyl-N-methyl-amino)-aniline in DMF andsubsequent treatment with sodium hydroxide solution in methanol.

[0663] Yield: 43% of theory,

[0664] Melting point: 230-235° C. (decomposition)

[0665] C₂₉H₃₀N₄O₂ (466.59)

[0666] Mass spectrum: M⁺=466

[0667] R_(f) value: 0.54 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[0668] C₂₉H₃₀N₄O₂ x 1.5H₂O (493.61)

[0669] Calc.: C, 70.57; H, 6.74; N, 11.35. Found: 70.57; 6.32; 11.28.

EXAMPLE 51

[0670](Z)-3-{1-[4-(N-morpholinomethylcarbonyl-N-methyl-amino)-phenylamino-1-phenyl-methylidene}-2-indolinone

[0671] Prepared analogously to Example 43 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-(N-morpholinomethylcarbonyl-N-methyl-amino)-aniline in DMF andsubsequent treatment with sodium hydroxide solution in methanol.

[0672] Yield: 99% of theory,

[0673] Melting point: 263-265° C.

[0674] C₂₈H₂₈N₄O₃ (468.56)

[0675] Mass spectrum: M⁺=468

[0676] Calc.: C, 71.78; H, 6.02; N, 11.96. Found: 70.75; 6.05; 11.90.

EXAMPLE 52

[0677](Z)-3-{1-[4-(N-(4-methylpiperazinomethylcarbonyl)-N-methyl-amino-phenylamino]-1-phenyl-methylidene}-2-indolinone

[0678] Prepared analogously to Example 43 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-[N-(4-methylpiperazinomethylcarbonyl)-N-methyl-amino]-aniline in DMFand subsequent treatment with sodium hydroxide solution in methanol.

[0679] Yield: 73% of theory,

[0680] Melting point: 277-278° C.

[0681] C₂₉H₃₁N₅O₂ (481.60)

[0682] Mass spectrum: M⁺=481

[0683] R_(f) value: 0.37 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

EXAMPLE 53

[0684](Z)-3-{1-[4-(N-(4-benzylpiperazinomethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[0685] Prepared analogously to Example 43 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-[N-(4-benzylpiperazinomethylcarbonyl)-N-methylamino]-aniline in DMFand subsequent treatment with sodium hydroxide solution in methanol.

[0686] Yield: 55% of theory,

[0687] Melting point: 157-158° C.

[0688] C₃₅H₃₅N₅O₂ (557.70)

[0689] Mass spectrum: M⁺=557

[0690] R_(f) value: 0.62 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[0691] C₃₅H₃₅N₅O₂ x H₂O (575.72)

[0692] Calc.: C, 73.02; H, 6.48; N, 12.16. Found: 73.10; 6.46; 12.13.

EXAMPLE 54

[0693](Z)-3-{1-[4-(N-piperazinomethylcarbonyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone-dihydrochloride

[0694] 390 mg (0.7 mmol) of(Z)-3-{1-[4-(N-(N-benzylpiperazinomethylcarbonyl)-N-methylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinoneare dissolved in 20 ml of dichloromethane and after the addition of 0.2g (1.4 mmol) of 1-chloroethyl chloroformate heated for 30 minutes atambient temperature and refluxed for 60 minutes. The solvent isconcentrated by evaporation, the residue is combined with 10 ml ofmethanol and refluxed for 90 minutes. After 18 hours stirring at ambienttemperature, the product is suction filtered, washed with methanol anddried.

[0695] Yield: 200 mg (51% of theory),

[0696] Melting point: 255-258° C. (decomposition)

[0697] C₂₈H₂₉N₅O₂ (467.58)

[0698] Mass spectrum: M⁺=467

[0699] C₂₈H₂₉N₅O₂ x 2HCl x H₂O (558.52)

[0700] Calc.: C, 60.22; H, 5.96; N, 12.54; Cl, 12.70. Found: 60.06;5.91; 12.53; 12.75.

EXAMPLE 55

[0701](Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0702] a)(Z)-3-[1-(4-cyanophenylamino)-1-phenyl-methylidene]-2-indolinone

[0703] Prepared analogously to Example 1 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-aminobenzonitrile in DMF and subsequent treatment with sodiumhydroxide solution.

[0704] Yield: 44% of theory,

[0705] Melting point: 293-295° C.

[0706] C₂₂H₁₅N₃O (337.38)

[0707] Calc.: C, 78.32; H, 4.48; N, 12.45. Found: 77.75; 4.68; 12.50.

[0708] b)(Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0709] 900 mg (2.7 mmol) of(Z)-3-[1-(4-cyanophenylamino)-1-phenyl-methylidene]-2-indolinone arehydrogenated in 200 ml of methanolic ammonia for 7 hours over 1.4 g ofRaney nickel at a hydrogen pressure of 3 bar. The catalyst is filteredoff, the solution is concentrated by evaporation and the residue isdivided between water/dichloromethane. The organic phase is dried,concentrated by evaporation, triturated with ether, suction filtered anddried.

[0710] Yield: 780 mg (83% of theory),

[0711] Melting point: 236-237° C.

[0712] C₂₂H₁₉N₃O (341.42)

[0713] Mass spectrum: M⁺=341

[0714] C₂₂H₁₉N₃O x 0.5H₂O (350.42)

[0715] Calc.: C, 75.41; H, 5.75; N, 11.99. Found: 75.08; 5.62; 11.81.

EXAMPLE 56

[0716](Z)-3-[1-(4-acetylaminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0717] Prepared analogously to Example 31 from(Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone,glacial acetic acid and acetic anhydride.

[0718] Yield: 135 mg (88% of theory),

[0719] Melting point: 207-210° C.

[0720] C₂₄H₂₁N₃O₂ (383.45)

[0721] Mass spectrum: M⁺=383

[0722] Calc.: C, 75.18; H, 5.52; N, 10.96. Found: 74.79; 5.46; 10.77.

EXAMPLE 57

[0723](Z)-3-[1-(4-tert.butoxycarbonylaminomethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene}-2-indolinone

[0724] Prepared analogously to Example 18 from(Z)-3-{1-[4-(aminomethyl)phenylamino]-1-phenyl-methylidene}-2-indolinone,N-tert.butoxycarbonyl-glycine, TBTU, HOBt andN-ethyl-N,N-diisopropylamine in DMF.

[0725] Yield: 85% of theory,

[0726] Melting point: 218-220° C.

[0727] C₂₉H₃₀N₄O₄ (498.59)

[0728] Mass spectrum: M⁺=498

[0729] Calc.: C, 69.86; H, 6.06; N, 11.24. Found: 69.40; 6.20; 11.18.

EXAMPLE 58

[0730](Z)-3-[1-(4-aminomethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone-hydrochloride

[0731] Prepared analogously to Example 29a from(Z)-3-[1-(4-tert.butoxycarbonylaminomethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinoneand ethyl acetate/hydrogen chloride in dichloromethane.

[0732] Yield: 88% of theory,

[0733] Melting point: 190-195° C.

[0734] C₂₄H₂₂N₄O₂ (398.47)

[0735] Mass spectrum: M⁺=398

[0736] C₂₄H₂₂N₄O₂ x HCl x H₂O (452.95)

[0737] Calc.: C, 63.64; H, 5.56; N, 12.37. Found: 64.11; 5.55; 12.19.

EXAMPLE 59

[0738](Z)-3-[1-(4-morpholinomethyl-phenylamino)-1-phenyl-methyli-den]-2-indolinone

[0739] Prepared analogously to Example 1 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-morpholinomethyl-aniline in DMF and subsequent treatment with sodiumhydroxide solution in methanol.

[0740] Yield: 66% of theory,

[0741] Melting point: 267-268° C.

[0742] C₂₆H₂₅N₃O₂ (411.51)

[0743] Mass spectrum: M⁺=411

[0744] R_(f) value: 0.58 (silica gel; ethyl acetate/petroleum ether=9:1)

[0745] Calc.: C, 75.89; H, 6.12; N, 10.21. Found: 75.18; 6.09; 10.14.

EXAMPLE 60

[0746] (Z)-3-[1-(4-acetylphenylamino)-1-phenyl-methylidene]-2-indolinone

[0747] Prepared analogously to Example 1 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-aminoacetophenone in DMF and subsequent treatment with sodiumhydroxide solution in methanol.

[0748] Yield: 20% of theory,

[0749] Melting point: 207-209° C.

[0750] C₂₃H₁₈N₂O₂ (354.41)

[0751] Mass spectrum: M⁺=354

[0752] R_(f) value: 0.24 (silica gel; dichloromethane/methanol=19:1)

EXAMPLE 61

[0753]3-{1-[N-(4-cyanophenyl)-N-methyl-amino]-1-phenyl-methylidene}-2-indolinone

[0754] Prepared analogously to Example 2 from1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and4-methylamino-benzonitrile in THF and subsequent treatment with sodiumhydroxide solution in methanol.

[0755] Yield: 6% of theory,

[0756] Melting point: 239° C.

[0757] C₂₃H₁₇N₃O (351.82)

[0758] Mass spectrum: M⁺=351

EXAMPLE 62

[0759](Z)-3-{1-[N-(4-amidinophenyl)-amino]-1-phenyl-methylidene}-2-indolinone-hydroacetate

[0760] 1.0 g (2.8 mmol) of(Z)-1-benzoyl-3-[1-(4-cyanophenylamino]-1-phenyl-methylidene]-2-indolinoneare dissolved in 20 ml of saturated methanolic hydrochloric acid andstirred for 18 hours at ambient temperature. The solvent is distilledoff, the residue is dissolved in 20 ml of absolute methanol and adjustedto pH 8 with conc. ammonia. The precipitate is suction filtered,suspended in methanol and refluxed for 2 hours with 0.4 g of ammoniumacetate. The product is suction filtered, washed with methanol anddried.

[0761] Yield: 340 mg (34% of theory),

[0762] Melting point: >260° C. (decomposition)

[0763] C₂₂H₁₈N₄O (354.41)

[0764] Mass spectrum: (M+H)⁺=355

[0765] R_(f) value: 0.44 (Reversed phase P8; water/acetonitrile=1:1+1%trifluoroacetic acid)

EXAMPLE 63

[0766] (Z)-3-[1-(3-cyanophenylamino-1-phenyl-methylidene]-2-indolinone

[0767] Prepared analogously to Example 9 from1-benzoyl-3-(1-chloro-1-phenyl-methylidene]-2-indolinone and3-aminobenzonitrile in THF and subsequent treatment with sodiumhydroxide solution in methanol.

[0768] Yield: 70% of theory,

[0769] Melting point: 262-272° C.

[0770] C₂₂H₁₅N₃O (337.38)

[0771] Mass spectrum: M⁺=337

EXAMPLE 64

[0772](Z)-3-[1-(3-amidinophenylamino)-1-phenyl-methylidene]-2-indolinone

[0773] Prepared analogously to Example 62 from(Z)-3-[1-(3-cyanophenylamino)-1-phenyl-methylidene]-2-indolinone andmethanolic hydrochloric acid in methanol and ammonium acetate.

[0774] Yield: 26% of theory,

[0775] Melting point: 235-237° C.

[0776] C₂₂H₁₈N₄O (354.41)

[0777] Mass spectrum: M⁺=354

EXAMPLE 65

[0778](Z)-3-{1-[3-(N-methylcarbamimidoyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[0779] Prepared analogously to Example 62 from(Z)-3-[1-(3-cyanophenylamino)-1-phenyl-methylidene]-2-indolinone,methanolic hydrochloric acid and methylamine in methanol.

[0780] Yield: 7% of theory,

[0781] Melting point: 248-250° C.

[0782] C₂₃H₂₀N₄O (368.44)

[0783] Mass spectrum: (M+H)⁺=369

[0784] R_(f) value: 0.23 (Reversed phase P8; methanol/5% salinesolution=6:4)

EXAMPLE 66

[0785](Z)-3-{1-[3-(N,N-dimethylcarbamimidoyl)-phenylamino)-1-phenyl-methylidene}-2-indolinone

[0786] Prepared analogously to Example 62 from(Z)-3-[1-(3-cyanophenylamino)-1-phenyl-methylidene]-2-indolinone,methanolic hydrochloric acid and dimethylamine in methanol.

[0787] Yield: 30% of theory,

[0788] Melting point: 238-242° C.

[0789] C₂₄H₂₂N₄O (382.47)

[0790] Mass spectrum: (M+H)⁺=383

[0791] R_(f) value: 0.27 (Reversed phase P8; methanol/5% salinesolution=6:4)

EXAMPLE 67

[0792](Z)-3-[1-(3-tert.butoxycarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0793] Prepared analogously to Example 9 from1-benzoyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and3-tert.butoxycarbonylaminomethyl-aniline in triethylamine.

[0794] Yield: 7% of theory,

[0795] Melting point: 190-195° C.

[0796] C₂₇H₂₇N₃O₃ (441.53)

[0797] Mass spectrum: M⁺=441

[0798] R_(f) value: 0.35 (silica gel; ethyl acetate/petroleum ether=1:1)

EXAMPLE 68

[0799](Z)-3-[1-(3-aminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0800] Prepared analogously to Example 57 from(Z)-3-[1-(3-tert.butoxycarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinoneand trifluoroacetic acid in dichloromethane.

[0801] Yield: 60% of theory,

[0802] Melting point: 175-185° C.

[0803] C₂₂H₁₉N₃O (341.42)

[0804] Mass spectrum: M⁺=341

[0805] R_(f) value: 0.44 (silica gel; ethylacetate/methanol/NH₄OH=4:1:0.5)

EXAMPLE 69

[0806] (Z)-3-[1-(3-aminophenylamino)-1-phenyl-methylidene]-2-indolinone

[0807] 3.5 g (0.01 mol) of(Z)-3-[1-(3-nitrophenylamino)-1-phenyl-methylidene}-2-indolinone aredissolved in 200 ml of THF and after the addition of 0.5 g ofpalladium/charcoal hydrogenated with hydrogen. Then the catalyst isfiltered off and concentrated by evaporation.

[0808] Yield: 3.4 g (99% of theory),

[0809] Melting point: 267-268° C.

[0810] C₂₁H₁₇N₃O (327.39)

[0811] Mass spectrum: M⁺=327

EXAMPLE 70

[0812](Z)-3-{1-[N-(4-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[0813] Prepared analogously to Example 69 from(Z)-3-[1-(4-nitrophenylamino)-1-phenyl-methylidene]-2-indolinone andpalladium/charcoal with hydrogen in THF.

[0814] Yield: 77% of theory,

[0815] Melting point: >290° C.

[0816] C₂₁H₁₇N₃O (327.39)

[0817] Mass spectrum: M⁺=327

[0818] R_(f) value: 0.51 (silica gel; dichloroethane/ethylacetate/glacial acetic acid=80:17:3)

EXAMPLE 71

[0819](Z)-3-[1-(3-guanidinophenylamino)-1-phenyl-methylidene]-2-indolinone

[0820] 2.0 g (6.1 mmol) of(Z)-3-[1-(3-aminophenylamino)-1-phenyl-methylidene]-2-indolinone and 1.0g (23.7 mmol) of cyanamide are dissolved in 100 ml of ethanol and 10 mlof ethereal hydrochloric acid and heated for 24 hours in a glass bomb at80° C. The solvent is distilled off. Chromatography of the residue onsilica gel (ethyl acetate/methanol/glacial acetic acid/water=17:3:5:5)yields the product.

[0821] Yield: 300 mg (13% of theory),

[0822] C₂₂H₁₉N₅O (369.43)

[0823] Mass spectrum: (M+H)⁺=370

EXAMPLE 72

[0824](Z)-3-[1-(4-guanidinophenylamino)-1-phenyl-methylidene]-2-in-dolinone

[0825] Prepared analogously to Example 71 from(Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone andcyanamide in dioxane/hydrogen chloride.

[0826] Yield: 27% of theory,

[0827] C₂₂H₁₉N₅O (369.43)

[0828] Mass spectrum: (M+H)⁺=370

[0829] R_(f) value: 0.27 (silica gel; methanol/water/glacial aceticacid=17:3:0.55)

EXAMPLE 73

[0830](Z)-1-methyl-3-[1-(3-cyanophenylamino)-1-phenyl-methylidene]-2-indolinone

[0831] a) 1-methyl-3-(1-hydroxy-1-phenyl-methylidene)-2-indolinone

[0832] 4.15 g (41 mmol) of diisopropylamine are placed in 50 ml of THF,cooled to −70° C. and combined with a solution of 14.4 ml of (36 mmol)of n-butyl lithium solution (2.5 mol in toluene) and stirred for 10minutes. Then a solution of 5.0 g (34 mmol) of 1-methyl-2-indolinone in30 ml of THF is added dropwise and stirred for 45 minutes at −70° C.Then 5.8 g (0.041 mol) of benzoylchloride are added dropwise. Thereaction solution is left to heat up slowly within 14 hours. It is thenpoured onto sodium chloride solution and extracted with ethyl acetate.The combined organic extracts are dried and concentrated by evaporation.The residue is chromatographed on silica gel(dichloromethane/methanol/ammonia=200:8:1).

[0833] Yield: 7.1 g (84% of theory),

[0834] Melting point: 145-147° C.

[0835] b)(Z)-1-methyl-3-[1-(3-cyanophenylamino)-1-phenyl-methylidene]-2-indolinone

[0836] Prepared analogously to Example 2 from1-methyl-3-(1-hydroxy-1-phenyl-methylidene)-2-indolinone, phosphoruspentachloride and 3-aminobenzonitrile.

[0837] Yield: 15% of theory,

[0838] Melting point: 158-160° C.

[0839] C₂₃H₁₇N₃O (351.41)

[0840] Mass spectrum: M⁺=351

[0841] R_(f) value: 0.42 (silica gel; dichloromethane/ethylacetate=100:3)

[0842] Calc.: C, 78.61; H, 4.88; N, 11.96. Found: 78.15; 4.89; 11.91.

EXAMPLE 74

[0843](Z)-3-[1-(4-dimethylaminomethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene}-2-indolinone

[0844] a) isocyanatomethyl-polystyrene resin

[0845] 18.2 g (31.5 mmol) of aminomethyl-polystyrene resin are allowedto swell in 200 ml of toluene for 45 minutes at ambient temperature. At5° C. 16.6 ml (0.31 mol) of phosgene solution (20% in toluene) areadded. Then the reaction solution is left for 100 minutes in anultrasound bath at 20° C. and then refluxed for 4 hours. After 18 hours'standing at ambient temperature the mixture is suction filtered, washedwith dichloromethane and ethyl acetate and dried.

[0846] Yield: 18.3 g (100% of theory).

[0847] b) 1-polystyrylmethylaminocarbonyl-2-indolinone

[0848] 13.3 g (0.1 mol) of 2-indolinone and 12.1 g (20.5 mmol) ofisocyanatomethyl-polystyrene resin are refluxed in 400 ml of toluene for12 hours. Then the mixture is cooled, washed with toluene, methylenechloride and methanol and dried.

[0849] Yield: 13.4 g (100% of theory).

[0850] c)3-(1-ethoxy-1-phenyl-methylidene)-1-polystyrylmethylamino-carbonyl-2-indolinone

[0851] 13.4 g (20.5 mmol) of1-polystyrylmethylaminocarbonyl-2-indolinone and 33.4 g (0.15 mol) oftriethyl orthobenzoate are refluxed in 200 ml of acetic anhydride for 22hours. Then the mixture is cooled, washed with ethyl acetate, methylenechloride and methanol and dried.

[0852] Yield: 14.3 g (100% of theory).

[0853] d)3-[1-(4-tert.butoxycarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-1-polystyrylmethylaminocarbonyl-2-indolinone

[0854] 710 mg (1 mmol) of3-(1-ethoxy-1-phenyl-methylidene)-1-polystyrylmethylaminocarbonyl-2-indolinoneare suspended in 15 ml of DMF and after the addition of 1.1 g (5 mmol)of 4-tert.butoxycarbonylamino-aniline heated to 120° C. for 11 hours.After 14 hours at ambient temperature the mixture is suction filtered,washed with dichloromethane and methanol and dried.

[0855] Yield: 770 mg (100% of theory).

[0856] e)3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-1-polystyrylmethylaminocarbonyl-2-indolinone

[0857] 770 mg (1 mmol) of(3-[1-(4-tert.butoxycarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-1-polystyrylmethylaminocarbonyl-2-indolinoneare sonicated in 10 ml of dichloromethane and 5 ml of trifluoroaceticacid for 2 hours in an ultrasound bath. The mixture is then suctionfiltered, washed with dichloromethane and methanol and dried.

[0858] Yield: 720 mg (100% of theory),

[0859] f)3-[1-(4-(dimethylaminomethylcarbonylaminomethyl-phenylami-no)-1-phenyl-methylidene]-1-polystyrylmethylaminocarbonyl-2-indolinone

[0860] 680 mg (1.0 mmol) of3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-1-polystyrylmethylaminocarbonyl-2-indolinone,1.6 g (5 mmol) of TBTU, 770 mg (5 mmol) of HOBt, 2.6 g (20 mmol) ofN-ethyl-N,N-diisopropylamine and 515 mg (5 mmol) of dimethylglycine aresonicated for 6 hours in 20 ml of dimethylformamide in an ultrasoundbath at 35° C. The mixture is then suction filtered, washed withdichloromethane and methanol and dried.

[0861] Yield: 570 mg (100% of theory),

[0862] g)(Z)-3-[1-(4-dimethylaminomethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0863] 560 mg (0.95 mmol) of3-[1-(4-(dimethylaminomethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-1-polystyrylmethylaminocarbonyl-2-indolinoneare heated to 90° C. in 20 ml of dioxane and 5 ml of 1N sodium hydroxidesolution for 7 hours. The mixture is then filtered and concentrated byevaporation. The residue is divided between dichloromethane/water, theorganic phase is dried and evaporated to dryness. The crude product istriturated with ethyl acetate and ether, suction filtered and dried.

[0864] Yield: 27 mg (7% of theory),

[0865] Melting point: 200-205° C.

[0866] C₂₆H₂₆N₄O₂ (426.52)

[0867] Mass spectrum: M⁺=426

[0868] R_(f) value: 0.60 (silica gel; dichloromethane/methanol=9:1)

EXAMPLE 75

[0869](Z)-3-{1-[4-(2-carboxy-ethylcarbonylaminomethyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[0870] Prepared analogously to Example 74 from(Z)-3-{1-[4-(2-carboxy-ethylcarbonylaminomethyl)-phenylamino]-1-phenyl-methylidene}-1-polystyrylmethylaminocarbonyl-2-indolinoneand sodium hydroxide solution in dioxane.

[0871] Yield: 5% of theory,

[0872] C₂₆H₂₃N₃O₄ (441.49)

[0873] Mass spectrum: (M−H)— =440

EXAMPLE 76

[0874](Z)-3-[1-(4-methoxymethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[0875] Prepared analogously to Example 74 from(Z)-3-[1-(4-methoxymethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-1-polystyrylmethylaminocarbonyl-2-indolinoneand sodium hydroxide solution in dioxane.

[0876] Yield: 6% of theory,

[0877] Melting point: 178-180° C.

[0878] C₂₅H₂₃N₃O₃ (413.48)

[0879] Mass spectrum: M⁺=413

EXAMPLE 77

[0880](Z)-3-[1-(4-chlorophenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0881] a) 1-acetyl-5-nitro-2-indolinone

[0882] 17.5 g (0.10 mol) of 1-acetyl-2-indolinone are dissolved in 100ml of conc. sulphuric acid and at −10° C. 8.8 g (0.11 mol) of ammoniumnitrate are added batchwise and stirred for 15 minutes. The reaction ispoured onto ice water, suction filtered and washed with water. Theresidue is distributed in ethyl acetate/water, the combined organicextracts are dried and concentrated by evaporation.

[0883] Yield: 20.5 g (93% of theory),

[0884] Melting point: 154-156° C.

[0885] b)1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indo-linone

[0886] 30.0 g (0.137 mol) of 1-acetyl-5-nitro-2-indolinone are dissolvedin 200 ml of acetic anhydride and after the addition of 50.0 g (0.274mol) of trimethyl orthobenzoate stirred for 3 hours at 100° C. Aftercooling it is evaporated down to half the quantity, diluted withether/petroleum ether, the precipitate is suction filtered and dried.

[0887] Yield: 40.9 g (88% of theory),

[0888] R_(f) value: 0.61 (silica gel; dichloromethane/petroleumether/ethyl acetate=4:5:1)

[0889] c)(Z)-3-[1-(4-chlorophenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0890] 0.5 g (1.5 mmol) of1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone aredissolved in 20 ml of dichloromethane and after the addition of 0.57 g(4.5 mmol) of 4-chloroaniline stirred for 72 hours at ambienttemperature. Then 3 ml of methanolic ammonia are added and stirred for48 hours. After removal of the solvent in vacuo the residue istriturated with ether, suction filtered and dried.

[0891] Yield: 150 mg (26% of theory),

[0892] C₂₁H₁₄ClN₃O₃ (391.82)

[0893] Mass spectrum: M⁺=393/391

[0894] R_(f) value: 0.68 (silica gel; dichloromethane/methanol=9:1)

EXAMPLE 78

[0895](Z)-3-[1-(4-methoxyphenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0896] Prepared analogously to Example 77 from1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-methoxyaniline in dichloromethane and methanolic ammonia.

[0897] Yield: 87% of theory,

[0898] C₂₂H₁₇N₃O₄ (387.40)

[0899] Mass spectrum: M⁺=387

[0900] R_(f) value: 0.66 (silica gel; dichloromethane/methanol=9:1)

EXAMPLE 79

[0901](Z)-3-[1-(4-trifluoromethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0902] Prepared analogously to Example 77 from1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone andtrifluoromethylanisidine in dichloromethane and subsequent treatmentwith methanolic ammonia.

[0903] Yield: 62% of theory,

[0904] C₂₂H₁₄F₃N₃O₃ (425.37)

[0905] Mass spectrum: M⁺=425

[0906] R_(f) value: 0.23 (silica gel; dichloromethane)

EXAMPLE 80

[0907](Z)-3-[1-(4-morpholinophenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0908] Prepared analogously to Example 77 from1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-morpholinoaniline in dichloromethane and subsequent treatment withmethanolic ammonia.

[0909] Yield: 68% of theory,

[0910] Melting point: >300° C.

[0911] C₂₅H₂₂N₄O₄ (442.48)

[0912] Mass spectrum: M⁺=442

[0913] R_(f) value: 0.56 (silica gel; ethylacetate/cyclohexane/methanol=1:1:0.2)

EXAMPLE 81

[0914](Z)-3-[1-(4-nitrophenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0915] Prepared analogously to Example 77 from1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-nitroaniline in DMF and subsequent treatment with methanolic ammonia.

[0916] Yield: 38% of theory,

[0917] C₂₁H₁₄N₄O₅ (402.37)

[0918] Mass spectrum: M⁺=402

[0919] R_(f) value: 0.65 (silica gel; dichloromethane/methanol 9:1)

EXAMPLE 82

[0920](Z)-3-[1-(4-Bromphenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0921] a)1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone

[0922] 5.07 g (23 mmol) of 5-nitro-2-indolinone are stirred for 2.5hours at 100° C. together with 15.5 g (69 mmol) of triethylorthobenzoate in 50 ml of acetic anhydride. After cooling, 100 ml ofether/petroleum ether (1:1) are added. The precipitate formed is suctionfiltered, washed with ether/petroleum ether (1:1) and dried.

[0923] Yield: 6.6 g (81% of theory),

[0924] Melting point: 233-234° C.

[0925](b)(Z)-3-[1-(4-Bromophenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0926] Prepared analogously to Example 77 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-bromoaniline in DMF with heating and subsequent treatment withpiperidine.

[0927] Yield: 92% of theory,

[0928] Melting point: 300-305° C.

[0929] C₂₁H₁₄BrN₃O₃ (436.27)

[0930] Mass spectrum: M⁺=437/435

[0931] R_(f) value: 0.33 (silica gel; dichloromethane/methanol=20:1)

[0932] Calc.: C, 57.82; H, 3.23; N, 9.63; Br, 18.32. Found: 57.81; 3.20;9.65; 18.22.

EXAMPLE 83

[0933](Z)-3-[1-(4-cyanophenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0934] Prepared analogously to Example 77 from1-benzoyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-aminobenzonitrile in DMF and subsequent treatment with methanolicammonia.

[0935] Yield: 33% of theory,

[0936] C₂₂H₁₄N₄O₃ (382.38)

[0937] Mass spectrum: M⁺=382

[0938] R_(f) value: 0.58 (silica gel; dichloromethane/methanol=9:1)

EXAMPLE 84

[0939](Z)-3-[1-(4-amidinophenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride

[0940] Prepared analogously to Example 77 from1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-aminobenzamidine in DMF.

[0941] Yield: 20% of theory,

[0942] C₂₂H₁₇N₅O₃ (399.41)

[0943] Mass spectrum: (M+H)⁺=400

[0944] R_(f) value: 0.07 (silica gel; dichloromethane/methanol=9:1)

EXAMPLE 85

[0945](Z)-3-[1-(3-cyanophenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0946] 2 g (5.2 mmol) of1-benzoyl-3-(1-hydroxy-1-phenyl-methylidene)-5-nitro-2-indolinone and1.8 g (16 mmol) of 3-aminobenzonitrile are stirred in DMF for 70 hoursat ambient temperature. Then the reaction solution is extracted withether, the organic phase is washed with water and dried over sodiumsulphate. After removal of the solvent in vacuo the residue ischromatographed on silica gel (dichloromethane/methanol=50:1).

[0947] Yield: 580 mg (23% of theory),

[0948] C₂₂H₁₄N₄O₃ (382.38)

[0949] Mass spectrum: M⁺=382

[0950] R_(f) value: 0.32 (silica gel; dichloromethane/methanol=50:1)

EXAMPLE 86

[0951](Z)-3-[1-(3-amidinophenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride

[0952] Prepared analogously to Example 77 from1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and3-aminobenzamidine in DMF.

[0953] Yield: 22% of theory,

[0954] C₂₂H₁₇N₅O₃ (399.41)

[0955] Mass spectrum: (M+H)⁺=400

[0956] R_(f) value: 0.17 (silica gel; dichloromethane/methanol=4:1)

EXAMPLE 87

[0957](Z)-3-[1-(4-methoxycarbonyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0958] Prepared analogously to Example 77 from1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone andmethyl 4-aminobenzoate in dichloromethane and subsequent treatment withmethanolic ammonia.

[0959] Yield: 10% of theory,

[0960] C₂₃H₁₇N₃O₅ (415.41)

[0961] Mass spectrum: M⁺=415

[0962] R_(f) value: 0.23 (silica gel; dichloromethane/methanol=50:1)

EXAMPLE 88

[0963](Z)-3-[1-(4-carboxy-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0964] Prepared analogously to Example 8 from(Z)-3-[1-(4-methoxycarbonyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinoneand sodium hydroxide solution in methanol.

[0965] Yield: 88% of theory,

[0966] C₂₂H₁₅N₃O₅ (401.38)

[0967] Mass spectrum: M⁺=401

[0968] R_(f) value: 0.52 (silica gel; dichloromethane/methanol=9:1)

EXAMPLE 89

[0969](Z)-3-[1-(3-acetylamino-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0970] a) 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone

[0971] 17.6 g (50 mmol) of1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone aresuspended in 200 ml of dichloromethane and 150 ml of ethanol. 75 ml of1N sodium hydroxide solution are added at 0° C. and the mixture is thenstirred for another 30 minutes at ambient temperature. The reactionsolution is evaporated down by half and 200 ml of water are then added.The product precipitated is suction filtered, washed with water,isopropanol and ether and dried.

[0972] Yield: 13.3 g (86% of theory),

[0973] Melting point: 239-240° C.

[0974] b)(Z)-3-[1-(3-acetylamino-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0975] Prepared analogously to Example 82 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and3-acetylamino-aniline in DMF.

[0976] Yield: 72% of theory,

[0977] Melting point: 318-320° C. (decomposition)

[0978] C₂₃H₁₈N₄O₄ (414.42)

[0979] Mass spectrum: M⁺=414

[0980] Calc.: C, 66.66; H, 4.38; N, 13.52. Found: 66.42; 4.46; 13.45.

EXAMPLE 90

[0981](Z)-3-[1-(4-tert.butoxycarbonylamino-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0982] Prepared analogously to Example 82 from1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-tert.butoxycarbonylamino-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[0983] Yield: 56% of theory,

[0984] Melting point: 235-237° C. (decomposition)

[0985] C₂₆H₂₄N₄O₅ (472.51)

[0986] Mass spectrum: M⁺=472

[0987] Calc.: C, 66.09; H, 5.12; N, 11.86. Found: 66.35; 5.19; 11.80.

EXAMPLE 91

[0988](Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0989] Prepared analogously to Example 29a from(Z)-3-[1-(4-tert.butoxycarbonylamino-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinoneand ethyl acetate/hydrogen chloride in dichloromethane.

[0990] Yield: 74% of theory,

[0991] Melting point: 269° C.

[0992] C₂₁H₁₆N₄O₃ (372.39)

[0993] Mass spectrum: M⁺=372

[0994] Calc.: C, 67.73; H, 14.33; N, 15.05. Found: 67.70; 4.48; 14.83.

EXAMPLE 92

[0995](Z)-3-[1-(4-formylamino-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0996] Prepared analogously to Example 29b from(Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene}-5-nitro-2-indolinoneand ethyl formate in DMF.

[0997] Yield: 89% of theory,

[0998] Melting point: 355-356° C. (decomposition)

[0999] C₂₂H₁₆N₄O₄ (400.40)

[1000] Mass spectrum: M⁺=400

[1001] Calc.: C, 66.00; H, 4.03; N, 13.99. Found: 65.59; 4.13; 13.85.

EXAMPLE 93

[1002](Z)-3-[1-(4-acetylamino-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1003] Prepared analogously to Example 31 from(Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinoneand acetic anhydride in glacial acetic acid.

[1004] Yield: 93% of theory,

[1005] Melting point: 328-330° C.

[1006] C₂₃H₁₈N₄O₄ (414.42)

[1007] Mass spectrum: M⁺=414

[1008] C₂₃H₁₈N₄O₄ x H₂O (432.44)

[1009] Calc.: C, 63.88; H, 4.66; N, 12.96. Found: 64.09; 4.68; 12.34.

EXAMPLE 94

[1010](Z)-3-[1-(4-dimethylaminomethylcarbonylamino-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1011] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-dimethylaminomethylcarbonylamino-aniline in DMF and subsequenttreatment with sodium hydroxide solution in methanol.

[1012] Yield: 63% of theory,

[1013] Melting point: 254-257° C.

[1014] C₂₅H₂₃N₅O₄ (457.49)

[1015] Mass spectrum: M⁺=457

[1016] Calc.: C, 65.64; H, 5.07; N, 15.31. Found: 65.20; 5.16; 14.99.

EXAMPLE 95

[1017](Z)-3-[1-(4-diethylaminomethylcarbonylamino-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride

[1018] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-diethylaminomethylcarbonylamino-aniline in DMF and subsequenttreatment with sodium hydroxide solution in methanol.

[1019] Yield: 54% of theory,

[1020] Melting point: 287-288

[1021] C₂₇H₂₇N₅O₄ (485.55)

[1022] Mass spectrum: M⁺=485

EXAMPLE 96

[1023](Z)-3-[1-(4-morpholinomethylcarbonylamino-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1024] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-morpholinomethylcarbonylamino-aniline in DMF and subsequent treatmentwith sodium hydroxide solution in methanol.

[1025] Yield: 88% of theory,

[1026] Melting point: 265-267° C.

[1027] C₂₇H₂₅N₅O₅ (499.53)

[1028] Mass spectrum: M⁺=499

[1029] C₂₇H₂₅N₅O₅ x H₂O (517.55)

[1030] Calc.: C, 62.60; H, 5.26; N, 13.53. Found: 62.68; 5.15; 13.57.

EXAMPLE 97

[1031](Z)-3-{1-[4-(4-methylpiperazinomethylcarbonylamino)-phenylami-no]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1032] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(4-methylpiperazinomethylcarbonylamino)-aniline in DMF and subsequenttreatment with sodium hydroxide solution in methanol.

[1033] Yield: 74% of theory,

[1034] Melting point: 232-233° C.

[1035] C₂₈H₂₈N₆O₄ (512.57)

[1036] Mass spectrum: M⁺=512

EXAMPLE 98

[1037](Z)-3-{1-[4-(N-acetyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1038] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(N-acetyl-N-methyl-amino)-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[1039] Yield: 82% of theory,

[1040] Melting point: 305-307° C.

[1041] C₂₄H₂₀N₄O₄ (428.45)

[1042] Mass spectrum: M⁺=428

[1043] Calc.: C, 67.28; H, 4.71; N, 13.08. Found: 67.05; 4.76; 12.94.

EXAMPLE 99

[1044](Z)-3-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-1-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1045] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-aniline in DMF andsubsequent treatment with sodium hydroxide solution in methanol.

[1046] Yield: 91% of theory,

[1047] Melting point: 295-297° C.

[1048] C₂₆H₂₅N₅O₄ (471.52)

[1049] Mass spectrum: M⁺=471

[1050] C₂₆H₂₅N₅O₄ x 0.5H₂O (480.5)

[1051] Calc.: C, 64.99; H, 5.45; N, 14.57. Found: 64.49; 5.51; 14.45.

EXAMPLE 100

[1052](Z)-3-{1[4-(N-diethylaminomethylcarbonyl-N-methyl-amino)-1-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1053] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(N-diethylaminomethylcarbonyl-N-methyl-amino)-aniline in DMF andsubsequent treatment with sodium hydroxide solution in methanol.

[1054] Yield: 40% of theory,

[1055] Melting point: 225° C.

[1056] C₂₈H₂₉N₅O₄ (499.57)

[1057] Mass spectrum: M⁺=499

[1058] Calc.: C, 67.37; H, 5.85; N, 14.02. Found: 66.99; 5.88; 13.98.

EXAMPLE 101

[1059](Z)-3-{1-[4-(N-piperidinomethylcarbonyl-N-methyl-amino)-1-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1060] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(N-piperidinomethylcarbonyl-N-methyl-amino)-aniline in DMF andsubsequent treatment with sodium hydroxide solution in methanol.

[1061] Yield: 80% of theory,

[1062] Melting point: 267-269° C.

[1063] C₂₉H₂₉N₅O₄ (511.59)

[1064] Mass spectrum: M⁺=511

[1065] R_(f) value: 0.55 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[1066] Calc.: C, 68.09; H, 5.71; N, 13.69. Found: 67.29; 5.58; 13.50.

EXAMPLE 102

[1067](Z)-3-{1-[4-(N-morpholinomethylcarbonyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1068] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(N-morpholinomethylcarbonyl-N-methyl-amino)-aniline in DMF andsubsequent treatment with sodium hydroxide solution in methanol.

[1069] Yield: 58% of theory,

[1070] Melting point: 293-295° C.

[1071] C₂₈H₂₇N₅O₅ (513.56)

[1072] Mass spectrum: M⁺=513

[1073] Calc.: C, 64.49; H, 5.30; N, 13.64. Found: 64.54; 5.25; 13.50.

EXAMPLE 103

[1074](Z)-3-{-[4-(N-(N-methylpiperazinomethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1075] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-[N-(N-methylpiperazinomethylcarbonyl)-N-methyl-amino]-aniline in DMFand subsequent treatment with sodium hydroxide solution in methanol.

[1076] Yield: 76% of theory,

[1077] Melting point: 239-241° C.

[1078] C₂₉H₃₀N₆O₄ (526.60)

[1079] Mass spectrum: M⁺=526

[1080] R_(f) value: 0.36 (silica gel; dichloromethane/methanol/NH₄OH9:1:0.1)

[1081] C₂₉H₃₀N₆O₄ x H₂O (544.61)

[1082] Calc.: C, 63.96; H, 5.92; N, 15.43. Found: 63.81; 5.95; 15.35.

EXAMPLE 104

[1083](Z)-3-{1′-[4-(N-(4-benzylpiperazinomethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1084] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-[N-(4-benzylpiperazinomethylcarbonyl)-N-methyl-amino)-aniline in DMFand subsequent treatment with sodium hydroxide solution in methanol.

[1085] Yield: 78% of theory,

[1086] Melting point: 201-203° C.

[1087] C₃₅H₃₄N₆O₄ (602.70)

[1088] Mass spectrum: M⁺=602

[1089] R_(f) value: 0.6 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[1090] C₃₅H₃₄N₆O₄ x 0.5H₂O (611.70)

[1091] Calc.: C, 69.75; H, 5.69; N, 13.94. Found: 68.73; 5.69; 13.52.

EXAMPLE 105

[1092](Z)-3-{1-[4-(N-piperazinomethylcarbonyl-N-methyl-amino)phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone-dihydrochloride

[1093] Prepared analogously to Example 54 from(Z)-3-{1-[4-(N-(4-benzylpiperazinomethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinoneand 1-chloroethyl chloroformate in dichloromethane.

[1094] Yield: 68% of theory,

[1095] Melting point: 246-248° C.

[1096] C₂₈H₂₈N₆O₄ (512.57)

[1097] Mass spectrum: M⁺=512

[1098] C₂₈H₂₈N₆O₄ x 2HCl (585.50)

[1099] Calc.: C, 57.44; H, 5.16; N, 14.35. Found: 57.00; 4.87; 14.09.

EXAMPLE 106

[1100](Z)-3-[1-(3-dimethylaminomethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1101] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and3-dimethylaminomethylcarbonylaminomethyl-aniline in DMF and subsequenttreatment with sodium hydroxide solution in methanol.

[1102] Yield: 64% of theory,

[1103] Melting point: 171-173° C.

[1104] C₂₆H₂₅N₅O₄ (471.52)

[1105] Mass spectrum: M⁺=471

[1106] Calc.: C, 66.23; H, 5.34; N, 14.85. Found: 65.97; 5.18; 14.79.

EXAMPLE 107

[1107](Z)-3-[1-(3-dimethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1108] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and3-dimethylaminomethyl-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[1109] Yield: 85% of theory,

[1110] Melting point: 214-217° C.

[1111] C₂₄H₂₂N₄O₃ (414.47)

[1112] Mass spectrum: M⁺=414

[1113] R_(f) value: 0.48 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[1114] Calc.: C, 69.55; H, 5.35; N, 13.52. Found: 69.55; 5.45; 13.38.

EXAMPLE 108

[1115](Z)-3-[1-(3-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1116] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and3-piperidinomethyl-aniline in DMF and subsequent treatment with sodiumhydroxide solution in methanol.

[1117] Yield: 95% of theory,

[1118] Melting point: 214-215° C.

[1119] C₂₇H₂₆N₄O₃ (454.53)

[1120] Mass spectrum: M⁺=454

[1121] Calc.: C, 71.35; H, 5.77; N, 12.33. Found: 70.85; 5.79; 12.28.

EXAMPLE 109

[1122](Z)-3-[1-(3-morpholinomethyl-phenylamino)-1-phenyl-methyli-den]-5-nitro-2-indolinone

[1123] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and3-morpholinomethyl-aniline in DMF and subsequent treatment with sodiumhydroxide solution in methanol.

[1124] Yield: 88% of theory,

[1125] Melting point: 272-275° C.

[1126] C₂₆H₂₄N₄O₄ (456.51)

[1127] Mass spectrum: M⁺=456

[1128] Calc.: C, 68.41; H, 5.30; N, 12.27. Found: 68.05; 5.21; 12.23.

EXAMPLE 110

[1129](Z)-3-{1-[3-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1130] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and3-(4-methylpiperazinomethyl)-aniline in DMF and subsequent treatmentwith sodium hydroxide solution in methanol.

[1131] Yield: 92% of theory,

[1132] Melting point: 256-258° C.

[1133] C₂₇H₂₇N₅O₃ (469.55)

[1134] Mass spectrum: M⁺=469

[1135] R_(f) value: 0.59 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[1136] Calc.: C, 69.07; H, 5.80; N, 14.92. Found: 68.86; 5.78; 14.96.

EXAMPLE 111

[1137](Z)-3-[1-(3-ethoxycarbonylmethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1138] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and3-ethoxycarbonylmethylaminomethyl-aniline in DMF.

[1139] Yield: 38% of theory,

[1140] Melting point: 130-133° C.

[1141] C₂₆H₂₄N₄O₅ (472.51)

[1142] Mass spectrum: M⁺=472

[1143] Calc.: C, 66.09; H, 5.12; N, 11.86. Found: 66.46; 5.32; 11.80.

EXAMPLE 112

[1144](Z)-3-{1-[3-(2-ethoxycarbonyl-ethylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1145] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and3-(2-ethoxycarbonyl-ethylaminomethyl)-aniline in DMF.

[1146] Yield: 70% of theory,

[1147] Melting point: 142-145° C.

[1148] C₂₇H₂₆N₄O₅ (486.53)

[1149] Mass spectrum: M⁺=486

[1150] Calc.: C, 66.66; H, 5.39; N, 11.52. Found: 66.44; 5.49; 11.43.

EXAMPLE 113

[1151](Z)-3-[1-(4-tert.butoxycarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1152] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-tert.butoxycarbonylaminomethyl-aniline in DMF and subsequent treatmentwith sodium hydroxide solution in methanol.

[1153] Yield: 89% of theory,

[1154] Melting point: 234-236° C. (decomposition)

[1155] C₂₇H₂₆N₄O₅ (486.53)

[1156] Mass spectrum: M⁺=486

[1157] Calc.: C, 66.66; H, 5.39; N, 11.52. Found: 66.98; 5.44; 11.42.

EXAMPLE 114

[1158](Z)-3-[1-(4-aminomethyl-phenylamino]-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride

[1159] Prepared analogously to Example 29a from(Z)-3-[1-(4-tert.butoxycarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinoneand ethyl acetate/hydrogen chloride.

[1160] Yield: 86% of theory,

[1161] Melting point: >370° C.

[1162] C₂₂H₁₈N₄O₃ (386.41)

[1163] Mass spectrum: M⁺=386

[1164] C₂₂H₁₈N₄O₃ x HCl x H₂O (440.89)

[1165] Calc.: C, 59.93; H, 4.80; N, 12.71. Found: 60.81; 4.66; 12.80.

EXAMPLE 115

[1166](Z)-3-[1-(4-aminomethylcarbonylaminomethyl-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone-hydrochloride

[1167] Prepared analogously to Example 29a from(Z)-3-[1-(4-tert.butoxycarbonylaminomethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinoneand ethyl acetate/hydrogen chloride.

[1168] Yield: 76% of theory,

[1169] Melting point: 225-228° C.

[1170] C₂₄H₂₁N₅O₄ (443.47)

[1171] Mass spectrum: M⁺=443

[1172] C₂₄H₂₁N₅O₄ x HCl x 1.5H₂O (506.95)

[1173] Calc.: C, 56.86; H, 4.97; N, 13.81. Found: 56.71; 4.91; 13.57.

EXAMPLE 116

[1174](Z)-3-[1-(4-methylaminomethylcarbonylaminomethyl-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone-hydrochloride

[1175] Prepared analogously to Example 29a from(Z)-3-{1-[4-(N-tert.butoxycarbonyl-N-methylamino)methylcarbonylaminomethyl-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinoneand ethyl acetate/hydrogen chloride.

[1176] Yield: 76% of theory,

[1177] Melting point: 195-198° C.

[1178] C₂₅H₂₃N₅O₄ (457.49)

[1179] Mass spectrum: M⁺=457

[1180] C₂₅H₂₃N₅O₄ x HCl x H₂O (511.97)

[1181] Calc.: C, 58.65; H, 5.12; N, 13.68. Found: 58.19; 4.96; 13.49.

EXAMPLE 117

[1182](Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1183] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-dimethylaminomethyl-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[1184] Yield: 73% of theory,

[1185] Melting point: 264-265° C.

[1186] C₂₄H₂₂N₄O₃ (414.47)

[1187] Mass spectrum: M⁺=414

[1188] Calc.: C, 69.55; H, 5.35; N, 13.52. Found: 69.29; 5.31; 13.33.

EXAMPLE 118

[1189](Z)-3-[1-(4-morpholinomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1190] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-morpholinomethyl-aniline in DMF and subsequent treatment with sodiumhydroxide solution in methanol.

[1191] Yield: 57% of theory,

[1192] Melting point: 273° C.

[1193] C₂₆H₂₄N₄O₄ (456.51)

[1194] Mass spectrum: M⁺=456

[1195] R_(f) value: 0.43 (silica gel; ethyl acetate/methanol=9:1)

[1196] C₂₆H₂₄N₄O₄ x H₂O (474.52)

[1197] Calc.: C, 65.81; H, 5.52; N, 11.81. Found: 65.24; 5.44; 11.62.

EXAMPLE 119

[1198](Z)-3-[1-(4-hexamethyleneiminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1199] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-hexamethyleneiminomethyl-aniline in DMF.

[1200] Yield: 64% of theory,

[1201] Melting point: 220° C.

[1202] C₂₈H₂₈N₄O₃ (468.56)

[1203] Mass spectrum: M⁺=468

[1204] R_(f) value: 0.25 (silica gel; ethyl acetate/methanol=8:2)

[1205] Calc.: C, 71.78; H, 6.02; N, 11.96. Found: 71.57; 6.12; 11.71.

EXAMPLE 120

[1206](Z)-3-{1-[4-(N-tert.butoxycarbonyl-N-methyl-aminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1207] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(N-tert.butoxycarbonyl-N-methyl-amino)methyl-aniline in DMF.

[1208] Yield: 60% of theory,

[1209] Melting point: 235

[1210] C₂₈H₂₈N₄O₅ (500.56)

[1211] Mass spectrum: M⁺=500

[1212] R_(f) value: 0.50 (silica gel; dichloromethane/ethyl acetate=7:3)

[1213] Calc.: C, 67.19; H, 5.64; N, 11.19. Found: 66.95; 5.68; 11.00.

EXAMPLE 121

[1214](Z)-3-[1-(4-methylaminomethyl-phenylamino)-1-phenyl-methyliden]-5-nitro-2-indolinone-hydrochloride

[1215] Prepared analogously to Example 29a from(Z)-3-{1-[4-(N-tert.butoxycarbonyl-N-methylamino)methyl-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinoneand ethyl acetate/hydrogen chloride.

[1216] Yield: 99% of theory,

[1217] Melting point: 351° C.

[1218] C₂₃H₂₀N₄O₃ (400.44)

[1219] Mass spectrum: M⁺=400

[1220] R_(f) value: 0.36 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[1221] C₂₃H₂₀N₄O₃ x HCl (436.91)

[1222] Calc.: C, 63.23; H, 4.84; N, 12.82. Found: 62.37; 4.78; 12.47.

EXAMPLE 122

[1223](Z)-3-{1-[4-(N-acetyl-N-methyl-aminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1224] Prepared analogously to Example 31 from(Z)-3-[1-(4-methylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinoneand acetic anhydride in glacial acetic acid.

[1225] Yield: 79% of theory,

[1226] Melting point: 307° C.

[1227] C₂₅H₂₂N₄O₄ (442.48)

[1228] Mass spectrum: M⁺=442

[1229] R_(f) value: 0.46 (silica gel; dichloromethane/methanol=9:1)

EXAMPLE 123

[1230](Z,S)-3-{1-[4-(1-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1231] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and(S)-4-(1-tert.butoxycarbonylamino-ethyl)-aniline in DMF.

[1232] Yield: 66% of theory,

[1233] Melting point: 247-249° C. (decomposition)

[1234] C₂₈H₂₈N₄O₅ (500.56)

[1235] Mass spectrum: M⁺=500

[1236] Calc.: C, 67.19; H, 5.64; N, 11.19. Found: 67.23; 5.56; 11.28.

EXAMPLE 124

[1237](Z,S)-3-{1-[4-(1-aminoethyl)-phenylamino]-1-phenyl-methyliden}-5-nitro-2-indolinone-hydrochloride

[1238] Prepared analogously to Example 29a from(Z,S)-3-{1-[4-(1-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinoneand ethyl acetate/hydrogen chloride.

[1239] Yield: 88% of theory,

[1240] Melting point: 230-235° C.

[1241] C₂₃H₂₀N₄O₃ (400.44)

[1242] Mass spectrum: M⁺=400

[1243] C₂₃H₂₀N₄O₃ x HCl x H₂O (454.92)

[1244] Calc.: C, 60.73; H, 5.10; N, 12.32. Found: 60.50; 5.09; 12.26.

EXAMPLE 125

[1245](Z,R)-3-{1-[4-(1-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1246] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and(R)-4-(1-tert.butoxycarbonylamino-ethyl)-aniline in DMF.

[1247] Yield: 88% of theory,

[1248] Melting point: 247-249° C.

[1249] C₂₈H₂₈N₄O₅ (500.56)

[1250] Mass spectrum: M⁺=500

[1251] Calc.: C, 67.19; H, 5.64; N, 11.19. Found: 67.38; 5.69; 11.25.

EXAMPLE 126

[1252](Z,R)-3-{1-[4-(1-aminoethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone-hydrochloride

[1253] Prepared analogously to Example 29a from(Z,R)-3-{1-[4-(1-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinoneand ethyl acetate/hydrogen chloride.

[1254] Yield: 91% of theory,

[1255] Melting point: 230-235° C.

[1256] C₂₃H₂₀N₄O₃ (400.44)

[1257] Mass spectrum: M⁺=400

[1258] C₂₃H₂₀N₄O₃ x HCl x H₂O (454.92)

[1259] Calc.: C, 60.73; H, 5.10; N, 12.32. Found: 60.87; 5.12; 12.35.

EXAMPLE 127

[1260](Z)-3-{1-[4-(2-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-phenyl-methylidene1-5-nitro-2-indolinone

[1261] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(1-tert.butoxycarbonylamino-ethyl)-aniline in DMF and subsequenttreatment with sodium hydroxide solution in methanol.

[1262] Yield: 92% of theory,

[1263] Melting point: 213-214° C.

[1264] C₂₈H₂₈N₄O₅ (500.56)

[1265] Mass spectrum: M⁺=500

[1266] Calc.: C, 67.19; H, 5.64; N, 11.19. Found: 66.46; 5.79; 11.02.

EXAMPLE 128

[1267](Z)-3-{1-[4-(2-aminoethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone-hydrochloride

[1268] Prepared analogously to Example 29a from(Z)-3-{1-[4-(2-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinoneand ethyl acetate/hydrogen chloride.

[1269] Yield: 90% of theory,

[1270] Melting point: 335-340° C. (decomposition)

[1271] C₂₃H₂₀N₄O₃ (400.44)

[1272] Mass spectrum: M⁺=400

[1273] C₂₃H₂₀N₄O₃ x HCl (436.91)

[1274] Calc.: C, 61.95; H, 4.97; N, 12.56. Found: 61.68; 5.00; 12.50.

EXAMPLE 129

[1275](Z)-3-{1-[4-(2-acetylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1276] Prepared analogously to Example 31 from(Z)-3-{1-[4-(2-aminoethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinoneand acetic anhydride in glacial acetic acid.

[1277] Yield: 88% of theory,

[1278] Melting point: 306-307° C.

[1279] C₂₅H₂₂N₄O₄ (442.48)

[1280] Mass spectrum: M⁺=442

[1281] C₂₅H₂₂N₄O₄ x 0.5H₂O (451.48)

[1282] Calc.: C, 66.51; H, 5.13; N, 12.41. Found: 66.71; 5.00; 12.23.

EXAMPLE 130

[1283](Z)-3-{1-[4-(2-diethylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1284] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(2-diethylamino-ethyl)-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[1285] Yield: 75% of theory,

[1286] Melting point: 167-168° C.

[1287] C₂₇H₂₈N₄O₃ (456.55)

[1288] Mass spectrum: (M+H)⁺=457

[1289] Calc.: C, 71.03; H, 6.18; N, 12.27. Found: 70.83; 6.10; 12.14.

EXAMPLE 131

[1290](Z)-3-{1-[4-(2-(N-(2-hydroxyethyl)-N-ethyl-amino)-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1291] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and{4-[2-(N-(2-hydroxyethyl)-N-ethyl-amino)-ethyl]-phenylamino}-aniline inDMF.

[1292] Yield: 68% of theory,

[1293] Melting point: 165-166° C.

[1294] C₂₇H₂₈N₄O₄ (472.55)

[1295] Mass spectrum: M⁺=472

[1296] R_(f) value: 0.42 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[1297] Calc.: C, 68.63; H, 5.97; N, 11.86. Found: 68.63; 5.99; 11.74.

EXAMPLE 132

[1298](Z)-3-{1-[4-(2-piperidinoethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1299] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(2-piperidinoethyl)-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[1300] Yield: 68% of theory,

[1301] Melting point: 236-237° C.

[1302] C₂₈H₂₈N₄O₃ (468.56)

[1303] Mass spectrum: M⁺=468

[1304] R_(f) value: 0.62 (silica gel;dichloromethane/methanol/NH₄OH=4:1:0.2)

[1305] C₂₈H₂₈N₄O₃ x 0.5H₂O (477.56)

[1306] Calc.: C, 70.42; H, 6.12; N, 11.73. Found: 70.97; 6.08; 11.70.

EXAMPLE 133

[1307](Z)-3-{1-[4-(2-morpholinoethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1308] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(2-morpholinoethyl)-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[1309] Yield: 87% of theory,

[1310] Melting point: 304-306° C.

[1311] C₂₇H₂₆N₄O₄ (470.53)

[1312] Mass spectrum: M⁺=470

[1313] R_(f) value: 0.3 (silica gel; dichloromethane/methanol=19:1)

[1314] Calc.: C, 68.92; H, 5.57; N, 11.91. Found: 68.68; 5.55; 11.90.

EXAMPLE 134

[1315](Z)-3-{1-[4-(2-dimethylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1316] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(2-dimethylamino-ethyl)-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[1317] Yield: 77% of theory,

[1318] Melting point: 238-240° C.

[1319] C₂₅H₂₄N₄O₃ (428.50)

[1320] Mass spectrum: M⁺=428

[1321] R_(f) value: 0.4 (silica gel; dichloromethane/methanol=9:1)

[1322] Calc.: C, 70.08; H, 5.65; N, 13.08. Found: 69.87; 5.64; 12.99.

EXAMPLE 135

[1323](Z)-3-{1-[4-(2-(4-methylpiperazino)-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1324] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-[2-(N-methylpiperazino)-ethyl]-aniline in DMF and subsequent treatmentwith sodium hydroxide solution in methanol.

[1325] Yield: 90% of theory,

[1326] Melting point: 238-240° C.

[1327] C₂₈H₂₉N₅O₃ (483.58)

[1328] Mass spectrum: (M+H)⁺=484

[1329] R_(f) value: 0.44 (silica gel; dichloromethane/methanol=9:1)

[1330] C₂₈H₂₉N₅O₃ x 0.5H₂O (492.58)

[1331] Calc.: C, 68.27; H, 6.14; N, 14.22. Found: 67.87; 6.15; 14.14.

EXAMPLE 136

[1332](Z)-3-[1-(3-tert.butoxycarbonylaminomethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1333] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and3-tert.butoxycarbonylaminomethylcarbonylaminomethyl-aniline in DMF andsubsequent treatment with sodium hydroxide solution in methanol.

[1334] Yield: 78% of theory,

[1335] Melting point: 228° C.

[1336] C₂₉H₂₉N₅O₆ (543.58)

[1337] Mass spectrum: M⁺=543

[1338] Calc.: C, 64.08; H, 5.38; N, 12.88. Found: 63.72; 5.45; 12.73.

EXAMPLE 137

[1339](Z)-3-[1-(3-aminomethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride

[1340] Prepared analogously to Example 29a from(Z)-3-[1-(3-tert.butoxycarbonylaminomethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinoneand ethyl acetate/hydrogen chloride.

[1341] Yield: 99% of theory,

[1342] Melting point: 309° C.

[1343] C₂₄H₂₁N₅O₄ (443.47)

[1344] Mass spectrum: M⁺=443

[1345] C₂₄H₂₁N₅O₄ x HCl x 0.5H₂O (488.94)

[1346] Calc.: C, 58.96; H, 4.74; N, 14.32. Found: 58.40; 4.74; 14.01.

EXAMPLE 138

[1347](Z)-3-[1-(3-acetylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1348] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and3-acetylaminomethyl-aniline in DMF.

[1349] Yield: 57% of theory,

[1350] Melting point: 238° C.

[1351] C₂₄H₂₀N₄O₄ (428.45)

[1352] Mass spectrum: M⁺=428

[1353] C₂₄H₂₀N₄O₄ x 0.5H₂O (437.46)

[1354] Calc.: C, 65.90; H, 4.84; N, 12.81. Found: 66.29; 4.80; 12.76.

EXAMPLE 139

[1355](Z)-3-{1-[4-(N-aminomethylcarbonyl-N-methyl-amino)-phenyl-amino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1356] a)(Z)-3-{1-[4-(N-phthalimidomethylcarbonyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1357] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(N-phthalimidomethylcarbonyl-N-methyl-amino)-aniline in DMF.

[1358] Yield: 99% of theory,

[1359] Melting point: 303-305° C.

[1360] C₃₂H₂₃N₅O₆ (573.57)

[1361] Mass spectrum: M⁺=573

[1362] C₃₂H₂₃N₅O₆ x H₂O (591.59)

[1363] Calc.: C, 64.97; H, 4.26; N, 11.84. Found: 64.74; 4.41; 11.59.

[1364] b)(Z)-3-{1-[4-(N-aminomethylcarbonyl-N-methyl-amino)phenylamino]1-phenyl-methylidene}-5-nitro-2-indolinone

[1365] 287 mg (0.5 mmol) of(Z)-3-{1-[4-(N-phthalimidomethylcarbonyl-N-methylamino)phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinoneare suspended in 20 ml of ethanol and 20 ml of dichloromethane and afterthe addition of 0.3 ml of 80% hydrazine hydrate solution stirred for 18hours at 50° C. The mixture is then cooled to ambient temperature, theinsoluble matter is suction filtered and the mother liquor isconcentrated by evaporation. The residue is chromatographed on silicagel (dichloromethane/methanol/ammonia=92:8:0.8) and the product is againtriturated with methanol, suction filtered and dried.

[1366] Yield: 220 mg (99% of theory),

[1367] Melting point: 255-256° C.

[1368] C₂₄H₂₁N₅O₄ (443.47)

[1369] Mass spectrum: M⁺=443

[1370] Calc.: C, 65.00; H, 4.77; N, 15.79. Found: 64.73; 4.91; 15.66.

EXAMPLE 140

[1371](Z)-3-{1-[4-(N-acetylaminomethylcarbonyl-N-methyl-amino)phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1372] Prepared analogously to Example 31 from(Z)-3-{1-[4-(N-aminomethylcarbonyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinoneand acetic anhydride in glacial acetic acid.

[1373] Yield: 83% of theory,

[1374] Melting point: 277-278° C.

[1375] C₂₆H₂₃N₅O₅ (485.50)

[1376] Mass spectrum: M⁺=485

[1377] R_(f) value: 0.6 (silica gel; ethylacetate/methanol/NH₄OH=8:2:0.1)

[1378] C₂₆H₂₃N₄O₅ x H₂O (503.52)

[1379] Calc.: C, 62.02; H, 5.00; N, 13.91. Found: 61.77; 5.01; 13.79.

EXAMPLE 141

[1380](Z)-3-[1-(4-morpholinomethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1381] Prepared analogously to Example 74 from(Z)-1-polystyrylmethylaminocarbonyl-3-{1-[4-(morpholinomethylcarbonyl-aminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinoneand sodium hydroxide solution in dioxane.

[1382] Yield: 33% of theory,

[1383] Melting point: 290-295° C.

[1384] C₂₈H₂₇N₅O₅ (513.56)

[1385] Mass spectrum: M⁺=513

[1386] Calc.: C, 65.49; H, 5.30; N, 13.64. Found: 65.09; 5.32; 13.46.

EXAMPLE 142

[1387](Z)-3-[1-(4-dimethylaminomethylcarbonylaminomethyl-phenylamino-1-phenyl-methylidene]-5-nitro-2-indolinone

[1388] Prepared analogously to Example 74 from(Z)-1-polystyrylmethylaminocarbonyl-3-{1-[4-(dimethylaminomethylcarbonyl-aminomethyl)phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinoneand sodium hydroxide solution in dioxane.

[1389] Yield: 32% of theory,

[1390] Melting point: 272-273° C.

[1391] C₂₆H₂₅N₅O₄ (471.52)

[1392] Mass spectrum: M⁺=471

[1393] R_(f) value: 0.55 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[1394] Calc.: C, 66.23; H, 5.34; N, 14.85. Found: 66.10; 5.35; 14.70.

EXAMPLE 143

[1395](Z)-3-[1-(4-acetylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1396] Prepared analogously to Example 74 from(Z)-1-polystyrylmethylamino-carbonyl-3-[1-(4-acetylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinoneand sodium hydroxide solution in dioxane.

[1397] Yield: 37% of theory,

[1398] Melting point: 345-346° C.

[1399] C₂₄H₂₀N₄O₄ (428.45)

[1400] Mass spectrum: M⁺=428

[1401] Calc.: C, 67.94; H, 4.79; N, 12.73. Found: 66.46; 4.87; 12.80.

EXAMPLE 144

[1402](Z)-3-[1-(4-tert.butoxycarbonylaminomethylcarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1403] Prepared analogously to Example 74 from(Z)-1-polystyrylmethylaminocarbonyl-3-{1-[4-(tert.butoxycarbonylaminomethylcarbonylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinoneand sodium hydroxide solution in dioxane.

[1404] Yield: 24% of theory,

[1405] Melting point: 219-221° C. (decomposition)

[1406] C₂₉H₂₉N₅O₆ (543.58)

[1407] Mass spectrum: M⁺=543

[1408] C₂₉H₂₉N₅O₆ x 0.5H₂O (552.59)

[1409] Calc.: C, 63.03; H, 5.47; N, 12.67. Found: 63.20; 5.35; 12.61.

EXAMPLE 145

[1410](Z)-3-{1-[4-((N-tert.butoxycarbonyl-N-methyl-amino)-methylcarbonylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1411] Prepared analogously to Example 74 from(Z)-1-polystyrylmethylaminocarbonyl-3-{1-[4-((N-tert.butoxycarbonyl-N-methyl-amino)-methylcarbonylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinoneand sodium hydroxide solution in dioxane.

[1412] Yield: 31% of theory,

[1413] Melting point: 225-227° C. (decomposition)

[1414] C₃₀H₃₁N₅O₆ (557.61)

[1415] Mass spectrum: M⁺=557

[1416] C₃₀H₃₁N₅O₆ x 0.5H₂O (566.62)

[1417] Calc.: C, 63.59; H, 5.69; N, 12.36. Found: 63.75; 5.31; 12.22.

EXAMPLE 146

[1418](Z)-3-[1-(4-tert.butoxycarbonylaminomethyl-phenylamino)-1-(4-phthalimidomethyl-phenyl)-methylidene]-1-acetyl-5-nitro-2-indolinone

[1419] a) tert.butyl 4-phthalimidomethyl-benzoate

[1420] b)

[1421] 18.5 g (0.1 mol) of phthalimide-potassium are suspended in 80 mlof DMF and combined with 22.5 g (0.09 mol) of tert.butyl4-bromomethyl-benzoate. The reaction solution is stirred for 16 hours atambient temperature and then stirred into 40 ml of water, extracted withethyl acetate and chromatographed on silica gel (toluene).

[1422] Yield: 17.9 g (60% of theory),

[1423] Melting point: 144-145° C.

[1424] C₂₀H₁₉NO₄ x 0.25H₂O (341.88)

[1425] Calc.: C, 70.26; H, 5.75; N, 4.10. Found: 70.10; 5.73; 4.11.

[1426] b) 4-phthalimidomethyl-benzoic acid

[1427] 337 mg (1.0 mmol) of tert.butyl 4-phthalimidomethyl-benzoate arestirred in 3 ml of trifluoroacetic acid for 45 minutes at ambienttemperature. Then the solvent is eliminated in vacuo.

[1428] Yield: 96% of theory,

[1429] Melting point: 260-262° C.

[1430] C₁₆H₁₁NO₄ (281.3)

[1431] Mass spectrum: M⁺=281

[1432] c)3-[1-hydroxy-1-(4-phthalimidomethyl-phenyl)-methylidene]-1-acetyl-5-nitro-2-indolinone

[1433] Prepared analogously to Example 2a from1-acetyl-5-nitro-2-indolinone and 4-phthalimidomethyl-benzoic acid,TBTU, HOBt and N-ethyl-N,N-diisopropyl-amine in DMF.

[1434] Yield: 75% of theory,

[1435] Melting point: 246-248° C. (decomposition)

[1436] R_(f) value: 0.55 (silica gel; dichloromethane/methanol=10:1)

[1437] d)3-[1-chloro-1-(4-phthalimidomethyl-phenyl)-methylidene]-1-acetyl-5-nitro-2-indolinone

[1438] Prepared analogously to Example 2b from3-[1-hydroxy-1-(4-phthalimidomethyl-phenyl)-methylidene]-1-acetyl-5-nitro-2-indolinoneand phosphorus pentachloride in toluene.

[1439] Yield: 65% of theory,

[1440] Melting point: 234-236° C. (decomposition)

[1441] C₂₆H₁₆ClN₃O₆ (501.9)

[1442] Calc.: C, 62.22; H, 3.21; N, 8.37; Cl, 7.06. Found: 62.25; 3.31;8.27; 7.20.

[1443] e)(Z)-3-[1-(4-tert.butoxycarbonylaminomethyl-phenylamino)-1-(4-phthalimidomethyl-phenyl)-methylidene]-1-acetyl-5-nitro-2-indolinone

[1444] Prepared analogously to Example 2c from3-[1-chloro-1-(4-phthalimidomethyl-phenyl)-methylidene]-1-acetyl-5-nitro-2-indolinone,4-tert.butoxycarbonylaminomethyl-aniline and triethylamine indichloromethane.

[1445] Yield: 47% of theory,

[1446] Melting point: 125° C. (decomposition)

[1447] C₃₈H₃₃N₅O₈ (687.71)

[1448] Mass spectrum: M⁺=687

EXAMPLE 147

[1449](Z)-3-{1-[4-tert.butoxycarbonylaminomethyl-phenylamino]-1-[4-(2-carboxyphenyl)-carbonylaminomethyl-phenyl]-methylidene}-5-nitro-2-indolinone

[1450] Prepared analogously to Example 1 from(Z)-3-[1-(4-tert.butyloxycarbonylaminomethyl-phenylamino)-1-(4-phthalimidomethyl-phenyl)-methylidene]-1-acetyl-5-nitro-2-indolinoneand sodium hydroxide solution in methanol.

[1451] Yield: 88% of theory,

[1452] Melting point: 138° C. (decomposition)

[1453] C₃₆H₃₃N₅O₈ (663.69)

[1454] Mass spectrum: (M+H)⁺=664

[1455] R_(f) value: 0.31 (silica gel; dichloromethane/methanol=10:1)

EXAMPLE 148

[1456](Z)-3-[1-(4-tert.butoxycarbonylaminomethyl-phenylamino)-1-(4-aminomethyl-phenyl)-methylidene]-5-nitro-2-indolinone

[1457] Prepared analogously to Example 139b from(Z)-3-[1-(4-tert.butoxycarbonylaminomethyl-phenylamino)-1-(4-phthalimidomethyl-phenyl)-methylidene]-1-acetyl-5-nitro-2-indolinoneand hydrazine hydrate solution in ethanol.

[1458] Yield: 42% of theory,

[1459] Melting point: 220-223° C.

[1460] C₂₈H₂₉N₅O₅ (515.57)

[1461] Mass spectrum: M⁺=515

[1462] R_(f) value: 0.61 (silica gel; dichloromethane/methanol=9:1)

EXAMPLE 149

[1463](Z)-3-[1-(4-aminomethyl-phenylamino]-1-(4-aminomethyl-phenyl)-methylidene]-5-nitro-2-indolinone-dihydrotrifluoroacetate

[1464] Prepared analogously to Example 29a from(Z)-3-[1-(4-tert.butoxycarbonylaminomethyl-phenylamino)-1-(4-aminomethyl-phenyl)-methylidene]-5-nitro-2-indolinoneand trifluoroacetic acid in dichloromethane.

[1465] Yield: 54% of theory,

[1466] Melting point: 265° C.

[1467] C₂₃H₂₁N₅O₃ (415.46)

[1468] Mass spectrum: M⁺=415

[1469] R_(f) value: 0.50 (Reversed phase P8; methanol/5% salinesolution=6:4)

[1470] C₂₃H₂₁N₅O₃ x 2C₂HF₃O₂ x 2H₂O (679.53)

[1471] Calc.: C, 47.72; H, 4.00; N, 10.30. Found: 47.69; 3.96; 10.39.

EXAMPLE 150

[1472](Z)-3-[1-(4-tert.butoxycarbonylaminomethyl-phenylamino)-1-(4-acetylaminomethyl-phenyl)-methylidene]-5-nitro-2-indolinone

[1473] Prepared analogously to Example 31 from(Z)-3-[1-(4-tert.butoxycarbonylaminomethyl-phenylamino)-1-(4-aminomethyl-phenyl)-methylidene]-5-nitro-2-indolinoneand acetic anhydride in dioxane.

[1474] Yield: 61% of theory,

[1475] Melting point: 234° C. (decomposition)

[1476] C₃₀H₃₁N₅O₆ (557.61)

[1477] Mass spectrum: M⁺=557

[1478] R_(f) value: 0.60 (silica gel; dichloromethane/methanol=20:1)

[1479] C₃₀H₃₁N₅O₆ x 0.25H₂O (562.12)

[1480] Calc.: C, 64.07; H, 5.70; N, 12.46. Found: 64.01; 5.70; 12.13.

EXAMPLE 151

[1481](Z)-3-[1-(4-aminomethyl-phenylamino)-1-(4-acetylaminomethyl-phenyl)-methylidene]-5-nitro-2-indolinone-dihydrotrifluoroacetate

[1482] Prepared analogously to Example 29a from(Z)-3-[1-(4-tert.butoxycarbonylaminomethyl-phenylamino)-1-(4-acetylaminomethyl-phenyl)-methylidene]-5-nitro-2-indolinoneand trifluoroacetic acid in dichloromethane.

[1483] Yield: 92% of theory,

[1484] Melting point: 239-241° C. (decomposition)

[1485] C₂₅H₂₃N₅O₄ (457.49)

[1486] Mass spectrum: M⁺=457

[1487] C₂₅H₂₃N₅O₄ x 2C₂HF₃O₂ x 0.5H₂O (694.55)

[1488] Calc.: C, 50.80; H, 3.67; N, 10.21. Found: 50.14; 3.77; 10.08.

EXAMPLE 152

[1489](Z)-3-[1-(4-acetylaminomethyl-phenylamino)-1-(4-acetylamino-methyl-phenyl)-methylidene]-5-nitro-2-indolinone-hydrotrifluoroacetate

[1490] Prepared analogously to Example 31 from(Z)-3-[1-(4-aminomethyl-phenylamino)-1-(4-acetylaminomethyl-phenyl)-methylidene]-5-nitro-2-indolinoneand acetic anhydride in dioxane.

[1491] Yield: 99% of theory,

[1492] Melting point: 126° C. (decomposition)

[1493] C₂₇H₂₅N₅O₅ (499.53)

[1494] Mass spectrum: M⁺=499

[1495] R_(f) value: 0.42 (silica gel;dichloromethane/methanol/NH₄OH=10:1:0.1)

EXAMPLE 153

[1496](Z)-3-[1-phenylamino-1-(4-phthalimidomethyl-phenyl)-methylidene]-5-nitro-2-indolinone

[1497] Prepared analogously to Example 146 from1-acetyl-3-[1-chloro-1-(4-phthalimidomethyl-phenyl)-methylidene]-5-nitro-2-indolinone,aniline, N-ethyl-N,N-diisopropyl-amine and DMF.

[1498] Yield: 18% of theory,

[1499] Melting point: 334-336° C. (decomposition)

[1500] C₃₀H₂₀N₄O₅ (516.52)

[1501] Mass spectrum: M⁺=516

[1502] R_(f) value: 0.30 (silica gel; toluene/acetone=4:1)

EXAMPLE 154

[1503](Z)-3-[1-phenylamino-1-(4-aminomethyl-phenyl)-methylidene]-5-nitro-2-indolinone

[1504] Prepared analogously to Example 140 from(Z)-3-[1-phenylamino-1-(4-phthalimidomethyl-phenyl)-methylidene]-5-nitro-2-indolinoneand hydrazine hydrate solution in ethanol.

[1505] Yield: 66% of theory,

[1506] Melting point: 332° C. (decomposition)

[1507] C₂₂H₁₈N₄O₃ (386.41)

[1508] Mass spectrum: (M+H)⁺=387

[1509] R_(f) value: 0.38 (silica gel;dichloromethane/methanol/NH₄OH=10:1:0.1)

EXAMPLE 155

[1510](Z)-3-{1-[4-(2-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-(4-aminomethyl-phenyl)-methylidene}-5-nitro-2-indolinone

[1511] Prepared analogously to Example 140 from(Z)-3-{1-[4-(2-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-(4-phthalimidomethyl-phenyl)-methylidene}-1-acetyl-5-nitro-2-indolinoneand hydrazine hydrate solution in ethanol.

[1512] Yield: 65% of theory,

[1513] Melting point: 215-217° C. (decomposition)

[1514] C₂₉H₃₁N₅O₅ (529.60)

[1515] Mass spectrum: M⁺=529

[1516] R_(f) value: 0.33 (silica gel; dichloromethane/methanol=10:1)

[1517] C₂₉H₃₁N₅O₅ x H₂O x C₈H₆N₂O₂ (628.70)

[1518] Calc.: C, 63.05; H, 5.77; N, 13.37. Found: 63.16; 5.73; 13.50.

EXAMPLE 156

[1519](Z)-3-{1-[4-(2-aminoethyl)-phenylamino]-1-(4-aminomethyl-phenyl)-methylidene}-5-nitro-2-indolinone-dihydrotrifluoroacetate

[1520] Prepared analogously to Example 29a from(Z)-3-{1-[4-(2-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-(4-aminomethyl-phenyl)-methylidene}-5-nitro-2-indolinoneand trifluoroacetic acid in dichloromethane.

[1521] Yield: 96% of theory,

[1522] Melting point: 230-232° C. (decomposition)

[1523] C₂₄H₂₃N₅O₃ (429.48)

[1524] Mass spectrum: 429

[1525] R_(f) value: 0.27 (silica gel;dichloromethane/methanol/NH₄OH=4:1:0.1)

[1526] C₂₄H₂₃N₅O₃ x 2C₂HF₃O₂ (657.53)

[1527] Calc.: C, 51.14; H, 3.83; N, 10.65. Found: 51.53; 4.05; 11.05.

EXAMPLE 157

[1528](Z)-3-{1-[4-(2-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-(4-acetylaminomethyl-phenyl)-methylidene}-5-nitro-2-indolinone

[1529] Prepared analogously to Example 31 from(Z)-3-{1-[4-(2-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-(4-aminomethyl-phenyl)-methylidene}-5-nitro-2-indolinoneand acetic anhydride in dioxane.

[1530] Yield: 53% of theory,

[1531] Melting point: 94° C. (decomposition)

[1532] C₃₁H₃₃N₅O₆ (571.64)

[1533] Mass spectrum: (M−H)— =570

[1534] R_(f) value: 0.52 (silica gel; dichloromethane/methanol=25:1)

[1535] C₃₁H₃₃N₅O₆ x H₂O (589.65)

EXAMPLE 158

[1536](Z)-3-{1-[4-(2-aminoethyl)-phenylamino]-1-(4-acetylaminomethyl-phenyl)-methylidene}-5-nitro-2-indolinone-dihydrotrifluoroacetate

[1537] Prepared analogously to Example 29a from(Z)-3-{1-[4-(2-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-(4-acetylaminomethyl-phenyl)-methylidene}-5-nitro-2-indolinoneand trifluoroacetic acid in dichloromethane.

[1538] Yield: 67% of theory,

[1539] Melting point: 229° C. (decomposition)

[1540] C₂₆H₂₅N₅O₄ (471.52)

[1541] Mass spectrum: 471

[1542] R_(f) value: 0.33 (silica gel;dichloromethane/methanol/NH₄OH=4:1:0.1)

[1543] C₂₆H₂₅N₅O₄ x C₂HF₃O₂ x 0.5H₂O (594.55)

[1544] Calc.: C, 56.56; H, 4.58; N, 11.78. Found: 56.33; 4.54; 11.62.

EXAMPLE 159

[1545](Z)-3-[1-(4-diethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1546] 846 mg (2.0 mmol) of(Z)-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochlorideare suspended in 20 ml of methanol and combined with 0.1 ml (2.5 mmol)of acetaldehyde. After 15 minutes stirring at ambient temperature 157 mg(2.5 mmol) of sodium cyanoborohydride are added. The mixture is stirredfor 16 hours at ambient temperature and then another 0.1 ml of (2.5mmol) of acetaldehyde and 157 mg (2.5 mmol) of sodium cyanoborohydrideare added. After 22 hours stirring at ambient temperature the reactionmixture is concentrated by evaporation and the residue taken up inwater/dichloromethane. Extraction with dichloromethane andchromatography on silica gel (dichloromethane/methanol/NH₄OH=93:7:0.7)yield the product.

[1547] Yield: 340 mg (38% of theory),

[1548] Melting point: 173-174° C.

[1549] C₂₆H₂₆N₄O₃ (442.52)

[1550] Mass spectrum: M⁺=442

[1551] R_(f) value: 0.4 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[1552] Calc.: C, 70.57; H, 5.92; N, 12.66. Found: 70.27; 5.90; 12.57.

EXAMPLE 160

[1553](Z)-3-[1-(4-ethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1554] Prepared analogously to Example 159 from(Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride,acetaldehyde and sodium cyanoborohydride in methanol.

[1555] Yield: 17% of theory,

[1556] Melting point: 220-223° C.

[1557] C₂₄H₂₂N₄O₃ (414.47)

[1558] Mass spectrum: M⁺=414

[1559] R_(f) value: 0.2 (silica gel; ethylacetate/methanol/NH₄OH=8:2:0.1)

[1560] C₂₄H₂₂N₄O₃ x 0.5H₂O (423.47)

[1561] Calc.: C, 68.07; H, 5.47; N, 13.23. Found: 68.55; 5.41; 13.15.

EXAMPLE 161

[1562](Z)-3-[1-(4-Dipropylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1563] Prepared analogously to Example 159 from(Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride,propionaldehyde and sodium cyanoborohydride in methanol.

[1564] Yield: 29% of theory,

[1565] Melting point: 160-162° C.

[1566] C₂₈H₃₀N₄O₃ (470.57)

[1567] Mass spectrum: M⁺=470

[1568] R_(f) value: 0.6 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[1569] C₂₈H₃₀N₄O₃ x 0.5H₂O (479.58)

[1570] Calc.: C, 70.13; H, 6.52; N, 11.68. Found: 69.80; 6.61; 11.65.

EXAMPLE 162

[1571](Z)-3-[1-(4-propylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1572] Prepared analogously to Example 159 from(Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride,propionaldehyde and sodium cyanoborohydride in methanol.

[1573] Yield: 12% of theory,

[1574] Melting point: 201-202° C.

[1575] C₂₅H₂₄N₄O₃ (428.50)

[1576] Mass spectrum: M⁺=428

[1577] R_(f) value: 0.4 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[1578] C₂₅H₂₄N₄O₃ x 0.5H₂O (437.50)

[1579] Calc.: C, 68.63; H, 5.76; N, 12.81. Found: 68.81; 5.87; 12.83.

EXAMPLE 163

[1580](Z)-3-[1-(4-Diisobutylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1581] Prepared analogously to Example 159 from(Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride,isobutyraldehyde and sodium cyanoborohydride in methanol.

[1582] Yield: 3% of theory,

[1583] Melting point: 204-207° C.

[1584] C₃₀H₃₄N₄O₃ (498.63)

[1585] Mass spectrum: M⁺=498

[1586] R_(f) value: 0.95 (silica gel; ethylacetate/methanol/NH₄OH=8:2:0.1)

EXAMPLE 164

[1587](Z)-3-[1-(4-isobutylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1588] Prepared analogously to Example 159 from(Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride,isobutyraldehyde and sodium cyanoborohydride in methanol.

[1589] Yield: 44% of theory,

[1590] Melting point: 208° C.

[1591] C₂₆H₂₆N₄O₃ (442.52)

[1592] Mass spectrum: M⁺=442

[1593] R_(f) value: 0.4 (silica gel; ethylacetate/methanol/NH₄OH=8:2:0.1)

[1594] Calc.: C, 70.57; H, 5.92; N, 12.66. Found: 70.03; 6.00; 12.42.

EXAMPLE 165

[1595](Z)-3-[1-(4-Dibutylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1596] Prepared analogously to Example 159 from(Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride,butyraldehyde and sodium cyanoborohydride in methanol.

[1597] Yield: 12% of theory,

[1598] Melting point: 175° C.

[1599] C₃₀H₃₄N₄O₃ (498.63)

[1600] Mass spectrum: M⁺=498

[1601] Calc.: C, 72.26; H, 6.87; N, 11.24. Found: 71.79; 6.91; 11.35.

EXAMPLE 166

[1602](Z)-3-[1-(4-butylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1603] Prepared analogously to Example 159 from(Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride,butyraldehyde and sodium cyanoborohydride in methanol.

[1604] Yield: 14% of theory,

[1605] Melting point: 183° C.

[1606] C₂₆H₂₆N₄O₃ (442.52)

[1607] Mass spectrum: M⁺=442

[1608] Calc.: C, 70.57; H, 5.97; N, 12.66. Found: 70.33; 6.04; 12.44.

EXAMPLE 167

[1609](Z)-3-[1-(4-methylsulphonylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1610] Prepared analogously to Example 74 from(Z)-3-[1-(4-methylsulphonylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-1-polystyrylmethylaminocarbonyl-2-indolinoneand sodium hydroxide solution in dioxane.

[1611] Yield: 16% of theory,

[1612] Melting point: 294-296° C.

[1613] C₂₃H₂₀N₄O₅S (464.50)

[1614] Mass spectrum: M⁺=464

[1615] C₂₃H₂₀N₄O₅S x H₂O (482.52)

[1616] Calc.: C, 57.25; H, 4.60; N, 11.61. Found: 57.56; 4.67; 11.70.

EXAMPLE 168

[1617](Z)-3-{1-[4-(4-hydroxypiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1618] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(4-hydroxypiperidinomethyl)-aniline in DMF.

[1619] Yield: 43% of theory,

[1620] Melting point: 155° C.

[1621] C₂₇H₂₆N₄O₄ (470.53)

[1622] Mass spectrum: M⁺=470

[1623] R_(f) value: 0.45 (silica gel; ethylacetate/methanol/NH₄OH=19:1:0.1)

[1624] C₂₇H₂₆N₄O₄ x 0.5H₂O (479.54)

[1625] Calc.: C, 67.63; H, 5.67; N, 11.68. Found: C 67.63; H, 5.63; N,11.59

EXAMPLE 169

[1626](Z)-3-{1-[4-(4-methylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1627] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(4-methylpiperidinomethyl)-aniline in DMF.

[1628] Yield: 92% of theory,

[1629] Melting point: 161° C.

[1630] C₂₈H₂₈N₄O₃ (468.56)

[1631] Mass spectrum: M⁺=468

[1632] R_(f) value: 0.3 (silica gel; ethyl acetate/methanol=9:1)

[1633] C₂₈H₂₈N₄O₃ x 0.5H₂O (477.57)

[1634] Calc.: C, 70.42; H, 6.12; N, 11.73. Found: 70.58; 6.25; 11.68.

EXAMPLE 170

[1635](Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1636] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-piperidinomethyl-aniline in DMF.

[1637] Yield: 77% of theory,

[1638] Melting point: 242-243° C.

[1639] C₂₇H₂₆N₄O₃ (454.53)

[1640] Mass spectrum: M⁺=454

[1641] R_(f) value: 0.3 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[1642] Calc.: C, 71.35; H, 5.77; N, 12.33. Found: 71.40; 6.00; 12.37.

EXAMPLE 171

[1643](Z)-3-{1-[4-(4-methoxypiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1644] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(4-methoxypiperidinomethyl)-aniline in DMF.

[1645] Yield: 48% of theory,

[1646] Melting point: 204-206° C.

[1647] C₂₈H₂₈N₄O₄ (484.56)

[1648] Mass spectrum: M⁺=484

[1649] R_(f) value: 0.5 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[1650] Calc.: C, 69.41; H, 5.82; N, 11.56. Found: 69.11; 5.83; 11.47.

EXAMPLE 172

[1651](Z)-3-{1-[4-(4-phenylmethyl-piperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1652] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(4-phenylmethyl-piperidino)methyl-aniline in DMF.

[1653] Yield: 48% of theory,

[1654] Melting point: 252° C.

[1655] C₃₄H₃₂N₄O₃ (544.66)

[1656] Mass spectrum: M⁺=544

[1657] Calc.: C, 74.98; H, 5.92; N, 10.29. Found: 74.52; 5.81; 10.23.

EXAMPLE 173

[1658](Z)-3-{1-[4-(4-hydroxy-4-phenyl-piperidinomethyl)-phenylamino-1-phenyl-methylidene}-5-nitro-2-indolinone

[1659] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(4-hydroxy-4-phenyl-piperidinomethyl)-aniline in DMF.

[1660] Yield: 68% of theory,

[1661] Melting point: 191-194° C.

[1662] C₃₃H₃₀N₄O₄ (546.63)

[1663] Mass spectrum: M⁺=546

[1664] R_(f) value: 0.4 (silica gel; ethylacetate/methanol/NH₄OH=95:5:0.5)

[1665] Calc.: C, 72.51; H, 5.53; N, 10.25. Found: 72.04; 5.50; 10.30.

EXAMPLE 174

[1666](Z)-3-{1-[4-(2-methoxyethylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1667] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(2-methoxyethylaminomethyl)-aniline in DMF.

[1668] Yield: 76% of theory,

[1669] Melting point: 184-185° C.

[1670] C₂₅H₂₄N₄O₄ (444.49)

[1671] Mass spectrum: (M+H]⁺=445

[1672] R_(f) value: 0.3 (silica gel; ethylacetate/methanol/NH₄OH=8:2:0.1)

[1673] Calc.: C, 67.56; H, 5.44; N, 12.60. Found: 67.10; 5.68; 12.31.

EXAMPLE 175

[1674](Z)-3-{1-[4-(4-ethylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1675] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(4-ethylpiperidinomethyl)-aniline in DMF.

[1676] Yield: 37% of theory,

[1677] Melting point: 225-227° C.

[1678] C₂₉H₃₀N₄O₃ (482.59)

[1679] Mass spectrum: [M+H]⁺=483

[1680] R_(f) value: 0.5 (silica gel; ethylacetate/methanol/NH₄OH=95:5:0.5)

[1681] C₂₉H₃₀N₄O₃ x 0.5H₂O (491.60)

[1682] Calc.: C, 70.86; H, 6.36; N, 11.40. Found: 71.09; 6.45; 11.32.

EXAMPLE 176

[1683](Z)-3-{1-[4-(4-ethoxycarbonyl-piperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1684] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(4-ethoxycarbonyl-piperidinomethyl)-aniline in DMF.

[1685] Yield: 63% of theory,

[1686] Melting point: 194° C.

[1687] C₃₀H₃₀N₄O₅ (526.60)

[1688] Mass spectrum: M⁺=526

[1689] Calc.: C, 68.43; H, 5.74; N, 10.64. Found: 68.19; 5.86; 10.49.

EXAMPLE 177

[1690](Z)-3-{1-[4-(4-carboxypiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1691] Prepared analogously to Example 8 by saponification of(Z)-3-{1-[4-(4-ethoxycarbonylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinonewith sodium hydroxide solution in ethanol.

[1692] Yield: 80% of theory,

[1693] Melting point: 207° C.

[1694] C₂₈H₂₆N₄O₅ (498.54)

[1695] Mass spectrum: M⁺=498

[1696] C₂₈H₂₆N₄O₅ x 0.5H₂O (507.55)

[1697] Calc.: C, 66.26; H, 5.36; N, 11.04. Found: 66.14; 5.38; 11.03.

EXAMPLE 178

[1698](Z)-3-{1-[4-(2-ethoxycarbonylmethylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1699] Prepared analogously to Examples 43 and 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(2-ethoxycarbonylmethylamino-ethyl)-aniline in DMF.

[1700] Yield: 57% of theory,

[1701] Melting point: 139-140° C.

[1702] C₂₇H₂₆N₄O₅ (486.53)

[1703] Mass spectrum: M⁺=486

[1704] R_(f) value: 0.5 (silica gel; ethyl acetate/methanol=9:1)

[1705] Calc.: C, 66.66; H, 5.39; N, 11.52. Found: 66.74; 5.10; 11.55.

EXAMPLE 179

[1706](Z)-3-[1-(4-cyanomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1707] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone,(4-aminophenyl)-acetonitrile in DMF and subsequent treatment withpiperidine.

[1708] Yield: 97% of theory,

[1709] Melting point: 329° C.

[1710] R_(f) value: 0.3 (silica gel; dichloromethane/methanol=25:1)

[1711] C₂₃H₁₆N₄O₃ x 0.3H₂O (401.81)

[1712] Calc.: C, 68.75; H, 4.16; N, 13.94. Found: 68.84; 4.13; 14.12.

EXAMPLE 180

[1713](Z)-3-[1-(4-methoxycarbonylmethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[1714] Prepared by reaction analogously to Example 62 from(Z)-3-[1-(4-cyanomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinonewith methanolic hydrochloric acid and 1,2-ethylenediamine.

[1715] Yield: 43% of theory,

[1716] Melting point: 238-240° C.

[1717] C₂₄H₁₉N₃O₅ (429.44)

[1718] Mass spectrum: (M+Na)⁺=452

[1719] R_(f) value: 0.8 (silica gel;dichloromethane/methanol/NH₄OH=4:1:0.1)

EXAMPLE 181

[1720](Z)-3-[1-(4-phenylsulphonylaminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[1721] Prepared analogously to Example 74 from(Z)-3-[1-(4-phenylsulphonylaminomethyl-phenylamino)-1-phenyl-methylidene]-1-polystyrylmethylaminocarbonyl-2-indolinoneand sodium hydroxide solution in dioxane.

[1722] Yield: 3% of theory,

[1723] C₂₈H₂₃N₃O₃S (481.58)

[1724] Mass spectrum: M⁺=481

EXAMPLE 182

[1725](Z)-3-[1-(4-methylsulphonylaminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone

[1726] Prepared analogously to Example 74 from(Z)-3-[1-(4-methylsulphonylaminomethyl-phenylamino)-1-phenyl-methylidene]-1-polystyrylmethylaminocarbonyl-2-indolinoneand sodium hydroxide solution in dioxane.

[1727] Yield: 8% of theory,

[1728] C₂₃H₂₁N₃O₃S (419.51)

[1729] Mass spectrum: M⁺=419

EXAMPLE 183

[1730](Z)-3-[1-(3-methylsulphonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[1731] Prepared analogously to Example 1 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and3-methylsulphonylamino-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[1732] Yield: 62% of theory,

[1733] Melting point: 275° C.

[1734] C₂₂H₁₉N₃O₃S (405.48)

[1735] Mass spectrum: M⁺=405

[1736] Calc.: C, 65.18; H, 4.72; N, 10.36. Found: 65.02; 4.95; 9.95.

EXAMPLE 184

[1737](Z)-3-{1-[3-(N-methyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[1738] Prepared analogously to Example 36 from(Z)-3-[1-(3-methylsulphonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone,methyliodide and potassium carbonate in acetone.

[1739] Yield: 96% of theory,

[1740] Melting point: 261° C.

[1741] C₂₃H₂₁N₃O₃S (419.51)

[1742] Mass spectrum: M⁺=419

EXAMPLE 185

[1743](Z)-3-[1-(4-methylsulphonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[1744] Prepared analogously to Example 1 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-methylsulphonylamino-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[1745] Yield: 4% of theory,

[1746] Melting point: 299-301° C.

[1747] C₂₂H₁₉N₃O₃S (405.48)

[1748] Mass spectrum: M⁺=405

[1749] R_(f) value: 0.27 (silica gel; dichloromethane/ethyl acetate=7:3)

EXAMPLE 186

[1750](Z)-3-{1-[4-(N-methyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[1751] Prepared analogously to Example 1 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-(N-methyl-N-methylsulphonyl-amino)-aniline in DMF and subsequenttreatment with sodium hydroxide solution in methanol.

[1752] Yield: 35% of theory,

[1753] Melting point: 269° C.

[1754] C₂₆H₂₈N₄O₃S (476.60)

[1755] Mass spectrum: M⁺=419

[1756] C₂₃H₂₁N₃O₃S x 0.3H₂O (424.91)

[1757] Calc.: C, 65.02; H, 5.12; N, 9.89. Found: 65.15; 5.07; 9.84.

EXAMPLE 187

[1758](Z)-3-{1-[4-(N-cyanomethyl-N-methylsulphonyl-amino)-phenyl-amino]-1-phenyl-methylidene}-2-indolinone

[1759] a) N-cyanomethyl-N-methylsulphonyl-4-nitroaniline

[1760] 3.24 g (15 mmol) of N-methylsulphonyl-4-nitroaniline aredissolved in 25 ml of DMSO and a total of 2.0 g (18 mmol) of potassiumtert.butoxide are added batchwise. After 1 hour stirring at ambienttemperature 2.7 g (23 mmol) of bromoacetonitrile are added dropwise.After 3 hours stirring at ambient temperature the mixture is poured ontoice water and extracted with ethyl acetate. The organic phase is washedwith water and the solvent is eliminated in vacuo. The residue thusobtained is recrystallised from ethanol.

[1761] Yield: 2.3 g (60% of theory),

[1762] Melting point: 116-118° C.

[1763] b) 4-(N-cyanomethyl-N-methylsulphonyl-amino)-aniline

[1764] Prepared analogously to Example 39c by catalytic hydrogenation ofN-cyanomethyl-N-methylsulphonyl-4-nitroaniline in DMF.

[1765] Yield: 62% of theory,

[1766] Melting point: 152-154° C.

[1767] c)(Z)-3-{1-[4-(N-cyanomethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[1768] Prepared analogously to Example 11 from3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-(N-cyanomethyl-N-methylsulphonyl-amino)-aniline in DMF.

[1769] Yield: 74% of theory,

[1770] Melting point: 266-268° C.

[1771] C₂₄H₂₀N₄O₃S (444.52)

[1772] Mass spectrum: M⁺=444

[1773] Calc.: C, 64.85; H, 4.53; N, 12.60. Found: 64.82; 4.25; 12.43.

EXAMPLE 188

[1774](Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-phenylamino-1-phenyl-methylidene}-2-indolinone

[1775] Prepared analogously to Example 1 and 187 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-[N-(2-dimethyamino-ethyl)-N-methylsulphonyl-amino]-aniline in DMF andsubsequent treatment with sodium hydroxide solution in methanol.

[1776] Yield: 42% of theory,

[1777] Melting point: 234-235° C.

[1778] C₂₆H₂₈N₄O₃S (476.60)

[1779] Mass spectrum: M⁺=476

[1780] Calc.: C, 65.52; H, 5.92; N, 11.76. Found: 65.43; 5.96; 11.78.

EXAMPLE 189

[1781](Z)-3-{1-[4-(N-(2-morpholinoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[1782] Prepared analogously to Examples 1 and 187 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-[N-(2-morpholinoethyl)-N-methylsulphonyl-amino]-aniline in DMF andsubsequent treatment with piperidine in methanol.

[1783] Yield: 60% of theory,

[1784] Melting point: 249-250° C.

[1785] C₂₈H₃₀N₄O₄S (518.64)

[1786] Mass spectrum: M⁺=518

[1787] C₂₈H₃₀N₄O₄S x 0.5H₂O (527.65)

[1788] Calc.: C, 63.74; H, 5.92; N, 10.62. Found: 63.89; 5.82; 10.55.

EXAMPLE 190

[1789](Z)-3-{1-[4-(N-carboxymethyl-N-methylsulphonyl-amino)-phenylamino-1-phenyl-methylidene}-2-indolinone

[1790] Prepared analogously to Examples 1 and 187 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-(N-ethoxycarbonylmethyl-N-methylsulphonyl-amino)-aniline in DMF andsubsequent treatment with sodium hydroxide solution in methanol.

[1791] Yield: 60% of theory,

[1792] Melting point: 247-250° C.

[1793] C₂₄H₂₁N₃O₅S (463.52)

[1794] Mass spectrum: M⁺=463

[1795] Calc.: C, 62.19; H, 14.57; N, 9.07. Found: 62.13; 4.64; 8.98.

EXAMPLE 191

[1796](Z)-3-{1-[4-(N-aminocarbonylmethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[1797] Prepared analogously to Example 18 from(Z)-3-{1-[4-(N-carboxymethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone,N-hydroxysuccinimide-ammonium salt, TBTU and triethylamine in DMF.

[1798] Yield: 48% of theory,

[1799] Melting point: 276-278° C.

[1800] C₂₄H₂₂N₄O₄S (462.53)

[1801] Mass spectrum: M⁺=462

[1802] R_(f) value: 0.5 (silica gel; dichloromethane/methanol=9:1)

[1803] C₂₄H₂₂N₄O₄S x 0.5H₂O (471.54)

[1804] Calc.: C, 61.13; H, 4.92; N, 11.88. Found: 61.26; 4.93; 11.47.

EXAMPLE 192

[1805](Z)-3-{1-[4-(N-methylaminocarbonylmethyl-N-methylsulphonyl-amino)-phenylamino1-phenyl-methylidene}-2-indolinone

[1806] Prepared analogously to Example 18 from(Z)-3-{1-[4-(N-carboxymethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone,methylammonium chloride, HOBt, TBTU and N-ethyl-N,N-diisopropylamine inDMF.

[1807] Yield: 77% of theory,

[1808] Melting point: 268-270° C.

[1809] C₂₅H₂₄N₄O₄S (476.56)

[1810] Mass spectrum: M⁺=476

[1811] Calc.: C, 63.01; H, 5.08; N, 11.76. Found: 62.83; 5.12; 11.60.

EXAMPLE 193

[1812](Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl-N-methylsulphonylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[1813] Prepared analogously to Example 18 from(Z)-3-{1-[4-(N-carboxymethyl-N-methylsulphonylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinone,dimethylammonium chloride, HOBt, TBTU and N-ethyl-N,N-diisopropylaminein DMF.

[1814] Yield: 85% of theory,

[1815] Melting point: 260-262° C.

[1816] C₂₆H₂₆N₄O₄S (490.59)

[1817] Mass spectrum: M⁺=490

[1818] Calc.: C, 63.66; H, 5.34; N, 11.42. Found: 63.52; 5.34; 11.37.

EXAMPLE 194

[1819](Z)-3-{1-[4-(N-(2-dimethylamino-ethylaminocarbonylmethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[1820] Prepared analogously to Example 18 from(Z)-3-{1-[4-(N-carboxymethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone,2-dimethylamino-ethylamine, HOBt, TBTU and N-ethyl-N,N-diisopropylaminein DMF.

[1821] Yield: 88% of theory,

[1822] Melting point: 214-216° C.

[1823] C₂₈H₃₁N₅O₄S (533.65)

[1824] Mass spectrum: M⁺=533

[1825] Calc.: C, 63.02; H, 5.85; N, 13.12. Found: 62.85; 5.89; 12.96.

EXAMPLE 195

[1826](Z)-3-{1-[4-(N-(3-ethoxycarbonyl-propyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[1827] Prepared analogously to Example 187 from3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-[N-(3-ethoxycarbonyl-propyl)-N-methyl-sulphonylamino]-aniline in DMF.

[1828] Yield: 60% of theory,

[1829] Melting point: 265-268° C.

[1830] C₂₈H₂₉N₃O₅S (519.62)

[1831] Mass spectrum: M⁺=519

[1832] Calc.: C, 64.72; H, 5.63; N, 8.09. Found: 64.82; 5.68; 8.01.

EXAMPLE 196

[1833](Z)-3-[(4-methylsulphonylamino-phenylamino)-1-phenyl-methylidene}-5-nitro-2-indolinone

[1834] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-methylsulphonylamino-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[1835] Yield: 74% of theory,

[1836] Melting point: 344-346° C.

[1837] C₂₂H₁₈N₄O₅S (450.48)

[1838] Mass spectrum: M⁺=450

[1839] Calc.: C, 58.66; H, 4.03; N, 12.44. Found: 58.22; 4.18; 12.44.

EXAMPLE 197

[1840](Z)-3-{1-[4-(N-methyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1841] Prepared analogously to Example 82 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(N-methyl-N-methyl-sulphonylamino)-aniline in DMF and subsequenttreatment with sodium hydroxide solution in methanol.

[1842] Yield: 91% of theory,

[1843] Melting point: 306-308° C.

[1844] C₂₃H₂₀N₄O₅S (464.50)

[1845] Mass spectrum: M⁺=464

[1846] Calc.: C, 59.47; H, 4.34; N, 12.06. Found: 59.45; 4.52; 12.10.

EXAMPLE 198

[1847](Z)-3-{-[4-(N-ethoxycarbonylmethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1848] Prepared analogously to Examples 89 and 187 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(N-ethoxycarbonylmethyl-N-methylsulphonyl-amino)-aniline in DMF.

[1849] Yield: 86% of theory,

[1850] Melting point: 236-238° C.

[1851] C₂₆H₂₄N₄O₇S (536.57)

[1852] Mass spectrum: M⁺=536

[1853] Calc.: C, 58.20; H, 4.51; N, 10.44. Found: 58.16; 4.69; 10.45.

EXAMPLE 199

[1854](Z)-3-{1-[4-(N-carboxymethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1855] Prepared analogously to Example 8 by saponification of(Z)-3-{1-[4-(N-ethoxycarbonylmethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinonewith sodium hydroxide solution in dioxane.

[1856] Yield: 89% of theory,

[1857] Melting point: 180-183° C.

[1858] C₂₄H₂₀N₄O₇S (508.51)

[1859] Mass spectrum: M⁺=508

[1860] C₂₄H₂₀N₄O₇S x 0.5C₄H₈O₂ (552.56)

[1861] Calc.: C, 56.52; H, 4.38; N, 10.14. Found: 56.52; 4.56; 9.96.

EXAMPLE 200

[1862](Z)-3-{1-[4-(N-methylaminocarbonylmethyl-N-methylsulphonyl-amino-phenylamino-1-phenyl-methylidene}-5-nitro-2-indolinone

[1863] Prepared analogously to Example 18 from(Z)-3-{1-[4-(N-carboxymethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone,methylammonium chloride, HOBt, TBTU and N-ethyl-diisopropylamine in DMF.

[1864] Yield: 47% of theory

[1865] Melting point: 267-268° C.

[1866] C₂₅H₂₃N₅O₆S (521.56)

[1867] Mass spectrum: M⁺=521

[1868] Calc.: C, 57.57; H, 4.44; N, 13.43. Found: 57.44; 4.69; 13.02.

EXAMPLE 201

[1869](Z)-3-{1′-[4-(N-dimethylaminocarbonylmethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1870] Prepared analogously to Example 18 from(Z)-3-{1-[4-(N-carboxymethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone,dimethylammonium chloride, HOBt, TBTU and N-ethyl-N,N-diisopropylaminein DMF.

[1871] Yield: 80% of theory,

[1872] Melting point: 277-280° C.

[1873] C₂₆H₂₅N₅O₆S (535.58)

[1874] Mass spectrum: (M+H)⁺=536

EXAMPLE 202

[1875](Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1876] Prepared analogously to Examples 1 and 187 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-aniline in DMF andsubsequent treatment with sodium hydroxide solution in methanol.

[1877] Yield: 86% of theory,

[1878] Melting point: 276-277° C.

[1879] C₂₆H₂₇N₅O₅S (521.60)

[1880] Mass spectrum: M⁺=521

[1881] Calc.: C, 59.87; H, 5.22; N, 13.43. Found: 60.03; 5.19; 13.39.

EXAMPLE 203

[1882](Z)-3-{1-[4-(N-(2-morpholinoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1883] Prepared analogously to Examples 1 and 187 from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-[N-(2-morpholinoethyl)-N-methylsulphonyl-amino]-aniline in DMF andsubsequent treatment with piperidine in methanol.

[1884] Yield: 62% of theory,

[1885] Melting point: 255-257° C.

[1886] C₂₈H₂₉N₅O₆S (563.64)

[1887] Mass spectrum: M⁺=563

[1888] Calc.: C, 59.67; H, 5.19; N, 12.43. Found: 59.20; 5.30; 12.18.

EXAMPLE 204

[1889](Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl-N-ethylsulphonyl-amino-phenylamino]-1-phenyl-methylidene}-2-indolinone

[1890] Prepared analogously to Examples 1 and 187 from(Z)-1-acetyl-3-[1-(4-ethylsulphonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone,bromoacetic acid-N,N-dimethylamide and potassium tert.butoxide in DMSOand subsequent treatment with sodium hydroxide solution in methanol.

[1891] Yield: 30% of theory,

[1892] Melting point: 206-208° C.

[1893] C₂₇H₂₈N₄O₄S (504.61)

[1894] Mass spectrum: M⁺=504

[1895] C₂₇H₂₈N₄O₄S x 0.5H₂O (513.62)

[1896] Calc.: C, 63.14; H, 5.69; N, 10.91. Found: 63.25; 5.62; 10.93.

EXAMPLE 205

[1897](Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl-N-phenylsulphonyl-amino]-phenylamino]-1-phenyl-methylidene}-2-indolinone

[1898] Prepared analogously to Examples 1 and 187 from(Z)-1-acetyl-3-[1-(4-phenylsulphonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone,bromoacetic acid-N,N-dimethylamide and potassium tert.butoxide in DMSOand subsequent treatment with sodium hydroxide solution in methanol.

[1899] Yield: 36% of theory,

[1900] Melting point: 255-258° C.

[1901] C₃₁H₂₈N₄O₄S (552.66)

[1902] Mass spectrum: M⁺=552

EXAMPLE 206

[1903](Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl-N-(p-tolylsulphonyl)-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[1904] Prepared analogously to Examples 1 and 187 from(Z)-1-acetyl-3-{1-[4-(p-tolylsulphonylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinone,bromoacetic acid-N,N-dimethylamide and potassium tert.butoxide in DMSOand subsequent treatment with sodium hydroxide solution in methanol.

[1905] Yield: 40% of theory,

[1906] Melting point: 223-226° C.

[1907] C₃₂H₃₀N₄O₄S (566.68)

[1908] Mass spectrum: M⁺=566

[1909] C₃₂H₃₀N₄O₄S x 0.5H₂O (575.68)

[1910] Calc.: C, 66.76; H, 5.43; N, 9.73. Found: 66.54; 5.49; 9.81.

EXAMPLE 207

[1911](Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl-N-benzylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[1912] Prepared analogously to Examples 1 and 187 from(Z)-1-acetyl-3-[1-(4-benzylsulphonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone,bromoacetic acid-N,N-dimethylamide and potassium tert.butoxide in DMSOand subsequent treatment with sodium hydroxide solution in methanol.

[1913] Yield: 77% of theory,

[1914] Melting point: 133-135° C.

[1915] C₃₂H₃₀N₄O₄S (566.68)

[1916] Mass spectrum: M⁺=566

[1917] C₃₂H₃₀N₄O₄S x H₂O (584.69)

[1918] Calc.: C, 65.74; H, 5.52; N, 9.58. Found: 65.62; 5.59; 9.53.

EXAMPLE 208

[1919](Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl-N-ethylsulphonyl-amino-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1920] Prepared analogously to Examples 82 and 187 from(Z)-1-acetyl-3-[1-(4-ethylsulphonylamino-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone,bromoacetic acid-N,N-dimethylamide and potassium tert.butoxide in DMSOand subsequent treatment with sodium hydroxide solution in methanol.

[1921] Yield: 27% of theory,

[1922] Melting point: 145-148° C.

[1923] C₂₇H₂₇N₅O₆S (549.61)

[1924] Mass spectrum: M⁺=549

[1925] R_(f) value: 0.42 (silica gel; dichloromethane/methanol=19:1)

[1926] Calc.: C, 59.01; H, 4.95; N, 12.74. Found: 59.20; 4.96; 12.26.

EXAMPLE 209

[1927](Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl-N-phenylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1928] Prepared analogously to Examples 82 and 187 from(Z)-1-acetyl-3-[1-(4-phenylsulphonylamino-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone,bromoacetic acid-N,N-dimethylamide and potassium tert.butoxide in DMSOand subsequent treatment with sodium hydroxide solution in methanol.

[1929] Yield: 13% of theory,

[1930] Melting point: 160-162° C.

[1931] C₃₁H₂₇N₅O₆S (597.65)

[1932] Mass spectrum: M⁺=597

EXAMPLE 210

[1933](Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl-N-(p-tolylsulphonyl)-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[1934] Prepared analogously to Examples 82 and 187 from(Z)-1-acetyl-3-{1-[4-(p-tolylsulphonylamino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone,bromoacetic acid-N,N-dimethylamide and potassium tert.butoxide in DMSOand subsequent treatment with sodium hydroxide solution in methanol.

[1935] Yield: 40% of theory,

[1936] Melting point: 198-200° C.

[1937] C₃₂H₂₉N₅O₆S (611.68)

[1938] Mass spectrum: M⁺=611

[1939] C₃₂H₂₉N₅O₆S x H₂O (629.69)

[1940] Calc.: C, 61.04; H, 4.96; N, 11.12. Found: 59.92; 4.53; 10.87.

EXAMPLE 211

[1941](Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-(p-tolyl)-methylidene]-2-indolinone

[1942] Prepared analogously to Example 2 from1-acetyl-3-[1-chloro-1-(p-tolyl)-methylidene)-2-indolinone and4-dimethylaminomethyl-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[1943] Yield: 27% of theory,

[1944] Melting point: 208-209° C.

[1945] C₂₅H₂₅N₃O (383.50)

[1946] Mass spectrum: M⁺=383

[1947] R_(f) value: 0.35 (silica gel; ethylacetate/methanol/NH₄OH=8:2:0.1)

[1948] C₂₅H₂₅N₃O x 0.3H₂O (388.89)

[1949] Calc.: C, 77.21; H, 6.63; N, 10.80. Found: 77.45; 6.39; 10.70.

EXAMPLE 212

[1950](Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-(p-tolyl)-methylidene]-5-nitro-2-indolinone

[1951] Prepared analogously to Example 2 from1-acetyl-3-[1-chloro-1-(p-tolyl)-methylidene)-5-nitro-2-indolinone and4-dimethylaminomethyl-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[1952] Yield: 84% of theory,

[1953] Melting point: 274-276° C.

[1954] C₂₅H₂₄N₄O₃ (428.49)

[1955] Mass spectrum: (M+H)⁺=429; (M−H)⁻=427; M⁺=428

[1956] R_(f) value: 0.5 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[1957] Calc.: C, 70.08; H, 5.65; N, 13.07. Found: 70.17; 5.50; 12.86.

EXAMPLE 213

[1958](Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-(m-tolyl)-methylidene]-2-indolinone

[1959] Prepared analogously to Example 2 from1-acetyl-3-[1-chloro-1-(m-tolyl)-methylidene)-2-indolinone and4-dimethylaminomethyl-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[1960] Yield: 36% of theory,

[1961] Melting point: 224-226° C.

[1962] C₂₅H₂₅N₃O (383.50)

[1963] Mass spectrum: M⁺=383

[1964] R_(f) value: 0.25 (silica gel; ethylacetate/methanol/NH₄OH=8:2:0.1)

[1965] Calc.: C, 77.30; H, 6.57; N, 10.96. Found: 77.27; 6.74; 10.74.

EXAMPLE 214

[1966](Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-(m-tolyl)-methylidene]-5-nitro-2-indolinone

[1967] Prepared analogously to Example 2 from1-acetyl-3-[1-chloro-1-(m-tolyl)-methylidene)-5-nitro-2-indolinone and4-dimethylaminomethyl-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[1968] Yield: 20% of theory,

[1969] Melting point: 210° C.

[1970] C₂₅H₂₄N₄O₃ (428.49)

[1971] Mass spectrum: M⁺=428

[1972] Calc.: C, 70.08; H, 5.65; N, 13.08. Found: 69.63; 5.94; 12.89.

EXAMPLE 215

[1973](Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-(4-methoxyphenyl)-methylidene]-2-indolinone

[1974] Prepared analogously to Example 2 from1-acetyl-3-[1-chloro-1-(4-methoxyphenyl)-methylidene)-2-indolinone and4-dimethylaminomethyl-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[1975] Yield: 46% of theory,

[1976] Melting point: 206-207° C.

[1977] C₂₅H₂₅N₃O₂ (399.50)

[1978] Mass spectrum: M⁺=399

[1979] R_(f) value: 0.3 (silica gel; ethylacetate/methanol/NH₄OH=8:2:0.1)

[1980] C₂₅H₂₅N₃O₂ x 0.5H₂O (408.50)

[1981] Calc.: C, 73.51; H, 6.42; N, 10.29. Found: 73.81; 6.58; 10.15.

EXAMPLE 216

[1982](Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-(4-methoxyphenyl)-methylidene]-5-nitro-2-indolinone

[1983] Prepared analogously to Example 2 from1-acetyl-3-[1-chloro-1-(4-methoxyphenyl)-methylidene)-5-nitro-2-indolinoneand 4-dimethylaminomethyl-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[1984] Yield: 76% of theory,

[1985] Melting point: 259-262° C.

[1986] C₂₅H₂₄N₄O₄ (444.49)

[1987] Mass spectrum: M⁺=444

[1988] R_(f) value: 0.6 (silica gel; dichloromethane/methanol=9:1)

[1989] Calc.: C, 67.56; H, 5.44; N, 12.60. Found: 67.49; 5.48; 12.39.

EXAMPLE 217

[1990](Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-(3-methoxyphenyl)-methylidene]-2-indolinone

[1991] Prepared analogously to Example 2 from1-acetyl-3-[1-chloro-1-(3-methoxyphenyl)-methylidene)-2-indolinone and4-dimethylaminomethyl-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[1992] Yield: 49% of theory,

[1993] Melting point: 193-194° C.

[1994] C₂₅H₂₅N₃O₂ (399.50)

[1995] Mass spectrum: M⁺=399

[1996] R_(f) value: 0.3 (silica gel; ethyl acetate/methanol/NH₄OH8:2:0.1)

[1997] Calc.: C, 75.16; H, 6.31; N, 10.52. Found: 75.16; 6.32; 10.59.

EXAMPLE 218

[1998](Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-(3-methoxyphenyl)-methylidene]-5-nitro-2-indolinone

[1999] Prepared analogously to Example 2 from1-acetyl-3-[1-chloro-1-(3-methoxyphenyl)-methylidene)-5-nitro-2-indolinoneand 4-dimethylaminomethyl-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[2000] Yield: 38% of theory,

[2001] Melting point: 206-208° C.

[2002] C₂₅H₂₄N₄O₄ (444.49)

[2003] Mass spectrum: M⁺=444

[2004] R_(f) value: 0.5 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[2005] Calc.: C, 67.56; H, 5.44; N, 12.60. Found: 67.12; 5.38; 12.33.

EXAMPLE 219

[2006](Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-(4-nitrophenyl)-methylidene]-2-indolinone

[2007] Prepared analogously to Example 2 from1-acetyl-3-[1-chloro-1-(4-nitrophenyl)-methylidene)-2-indolinone and4-dimethylaminomethyl-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[2008] Yield: 39% of theory,

[2009] Melting point: 235° C.

[2010] C₂₄H₂₂N₄O₃ (414.47)

[2011] Mass spectrum: M⁺=414

[2012] R_(f) value: 0.5 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[2013] Calc.: C, 69.55; H, 5.35; N, 13.52. Found: 69.52; 5.58; 13.42.

EXAMPLE 220

[2014](Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-(4-nitrophenyl)-methylidene]-5-nitro-2-indolinone

[2015] Prepared analogously to Example 2 from1-acetyl-3-[1-chloro-1-(4-nitrophenyl)-methylidene)-5-nitro-2-indolinoneand 4-dimethylaminomethyl-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[2016] Yield: 22% of theory,

[2017] Melting point: 233° C.

[2018] C₂₄H₂₁N₅O₅ (459.47)

[2019] Mass spectrum: M⁺=459

[2020] Calc.: C, 62.74; H, 4.61; N, 15.24. Found: 62.60; 4.91; 15.33.

EXAMPLE 221

[2021](Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-(4-chlorophenyl)-methylidene]-2-indolinone

[2022] Prepared analogously to Example 2 from1-acetyl-3-[1-chloro-1-(4-chlorphenyl)-methylidene)-2-indolinone and4-dimethylaminomethyl-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[2023] Yield: 46% of theory,

[2024] Melting point: 213° C.

[2025] C₂₄H₂₂ClN₃O (403.92)

[2026] Mass spectrum: M⁺=405/403

[2027] R_(f) value: 0.4 (silica gel; ethylacetate/methanol/NH₄OH=8:2:0.1)

[2028] C₂₄H₂₂ClN₃O x 0.5H₂O (412.92)

[2029] Calc.: C, 69.81; H, 5.61; N, 10.18. Found: 70.06; 5.87; 10.13.

EXAMPLE 222

[2030](Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-(4-chlorophenyl)-methylidene]-5-nitro-2-indolinone

[2031] Prepared analogously to Example 2 from1-acetyl-3-[1-chloro-1-(4-chlorophenyl)-methylidene)-5-nitro-2-indolinoneand 4-dimethylaminomethyl-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[2032] Yield: 36% of theory,

[2033] Melting point: 311° C.

[2034] C₂₄H₂₁ClN₄O₃ (448.91)

[2035] Mass spectrum: M⁺=450/448

[2036] R_(f) value: 0.85 (silica gel; dichloromethane/methanol=8:2)

[2037] Calc.: C, 64.21; H, 4.71; N, 12.48. Found: 64.13; 4.73; 12.20.

EXAMPLE 223

[2038](Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-(3-chlorophenyl)-methylidene]-2-indolinone

[2039] Prepared analogously to Example 2 from1-acetyl-3-[1-chloro-1-(3-chlorophenyl)-methylidene)-2-indolinone and4-dimethylaminomethyl-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[2040] Yield: 14% of theory,

[2041] Melting point: 197-198° C.

[2042] C₂₄H₂₂ClN₃O (403.92)

[2043] Mass spectrum: M⁺=405/403

[2044] C₂₄H₂₂ClN₃O x 0.5H₂O (412.92)

[2045] Calc.: C, 69.81; H, 5.61; N, 10.18. Found: 69.74; 5.63; 10.07.

EXAMPLE 224

[2046](Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-(3-chlorophenyl)-methylidene]-5-nitro-2-indolinone

[2047] Prepared analogously to Example 2 from1-acetyl-3-[1-chloro-1-(3-chlorophenyl)-methylidene)-5-nitro-2-indolinoneand 4-dimethylaminomethyl-aniline in DMF and subsequent treatment withsodium hydroxide solution in methanol.

[2048] Yield: 20% of theory,

[2049] Melting point: 274° C.

[2050] C₂₄H₂₁ClN₄O₃ (448.91)

[2051] Mass spectrum: M⁺=450/448

[2052] C₂₄H₂₁ClN₄O₃ x 0.5H₂O (457.92)

[2053] Calc.: C, 62.95; H, 4.84; N, 12.24. Found: 62.97; 4.81; 12.29.

EXAMPLE 225

[2054](Z)-3-{1-[4-(2-tert.butoxycarbonylamino-2-methoxycarbonyl-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2055] Prepared analogously to Example 89.

[2056] Melting point: 139° C.

[2057] C₃₀H₃₀N₄O₇ (558.60)

[2058] Mass spectrum: M⁺=558

[2059] Calc.: C, 64.51; H, 5.41; N, 10.03. Found: 64.02; 5.56; 9.98.

EXAMPLE 226

[2060](Z)-3-{1-[4-(2-tert.butoxycarbonylamino-2-carboxy-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2061] Prepared analogously to Example 8.

[2062] Melting point: 235° C. (decomposition)

[2063] C₂₉H₂₈N₄O₇ (544.57)

[2064] Mass spectrum: M⁺=544

[2065] C₂₉H₂₈N₄O₇ x H₂O (562.59)

[2066] Calc.: C, 61.01; H, 5.37; N, 9.96. Found: 62.45; 5.40; 10.06.

EXAMPLE 227

[2067](Z)-3-{1-[4-(2-amino-2-methoxycarbonyl-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone-hydrochloride

[2068] Prepared analogously to Example 29a.

[2069] Melting point: 215° C. (decomposition)

[2070] C₂₅H₂₂N₄O₅ (458.48)

[2071] Mass spectrum: M⁺=458

[2072] C₂₅H₂₂N₄O₅ x HCl x H₂O (521.96)

[2073] Calc: C, 57.53; H, 5.02; N, 10.73. Found: 57.54; 5.13; 10.59.

EXAMPLE 228

[2074](Z)-3-{1-[4-(2-amino-2-carboxy-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone-hydrochloride

[2075] Prepared analogously to Example 29a.

[2076] Melting point: 225° C. (decomposition)

[2077] C₂₄H₂₀N₄O₅ (444.45)

[2078] Mass spectrum: [M−CO₂ ⁺=400

[2079] C₂₄H₂₀N₄O₅ x HCl x 2H₂O (516.94)

[2080] Calc: C, 55.76; H, 4.87; N, 10.84. Found: 55.81; 5.15; 10.82.

EXAMPLE 229

[2081](Z)-3-[1-(4-thiomorpholinomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[2082] Prepared analogously to Example 89.

[2083] Melting point: 276-277° C.

[2084] C₂₆H₂₄N₄O₃S (472.57)

[2085] Mass spectrum: M⁺=472

[2086] Calc.: C, 66.08; H, 5.12; N, 11.86. Found: 65.89; 5.24; 11.84.

EXAMPLE 230

[2087](Z)-3-{1-[4-((1-oxothiomorpholino)-methyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2088] a) 4-(4-nitrophenylmethyl)-thiomorpholine-1-oxide

[2089] 11.7 g (58 mmol) of m-chloroperbenzoic acid are added to asolution of 11.5 g (48 mmol) of 4-(4-nitrophenylmethyl)-thiomorpholinein 100 ml of dichloromethane at ambient temperature. The reactionsolution is stirred for 4 hours at ambient temperature and then washedwith 1N sodium hydroxide solution and water and evaporated to dryness.Chromatography on silica gel (dichloromethane/methanol=9:1) yields theproduct.

[2090] Yield: 3.9 g (32% of theory),

[2091] C₁₁H₁₄N₂O₃S (254.31)

[2092] Mass spectrum: M⁺=254

[2093] b) 4-(4-aminophenylmethyl)-thiomorpholine-1-oxide

[2094] 1.2 g of Raney nickel are added to a solution of 3.9 g (15 mmol)of 4-(4-nitrophenylmethyl)-thiomorpholine-1-oxide in 10 ml ofdichloromethane and 40 ml of methanol. The mixture is hydrogenated undera hydrogen atmosphere. The product is obtained by chromatography onsilica gel (dichloromethane/methanol=9:1).

[2095] Yield: 1.8 g (51% of theory).

[2096] c)(Z)-3-{1-[4-((1-oxo-thiomorpholino)-methyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2097] Prepared analogously to Example 89.

[2098] Melting point: 289-290° C.

[2099] C₂₆H₂₄N₄O₄S (488.57)

[2100] Mass spectrum: M⁺=488

[2101] Calc.: C, 63.92; H, 4.95; N, 11.47. Found: 63.90; 5.09; 11.41.

EXAMPLE 231

[2102](Z)-3-{1-[4-((1,1-dioxothiomorpholino)-methyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2103] a) 4-(4-nitrophenylmethyl)-thiomorpholine-1,1-dioxide

[2104] 8.6 g (40 mmol) of 4-nitrobenzylbromide are dissolved in 100 mlof acetone. 6.9 g (50 mmol) of potassium carbonate and 5.4 g (40 mmol)of thiomorpholine-1,1-dioxide are added. The reaction solution isstirred for 7 hours at ambient temperature. After the undissolved solidshave been filtered off, the solution is concentrated by evaporation. Theresidue is divided between ethyl acetate and water. The organic phasesare freed from solvent in vacuo. The product is triturated with etherand dried.

[2105] Yield: 7.2 g (67% of theory),

[2106] Melting point: 181-182° C.

[2107] b) 4-(4-aminophenylmethyl)-thiomorpholine-1,1-dioxide

[2108] Prepared analogously to Example 230b.

[2109] Melting point: 171-172° C.

[2110] c)(Z)-3-{1-[4-((1,1-dioxothiomorpholino)-methyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2111] Prepared analogously to Example 89.

[2112] Melting point: 328-329° C. (decomposition)

[2113] C₂₆H₂₄N₄O₅S (504.57)

[2114] Mass spectrum: M⁺=504

[2115] Calc.: C, 61.89; H, 4.79; N, 11.10. Found: 61.90; 5.03; 11.10.

EXAMPLE 232

[2116](Z)-3-{1-[4-(N-cyclohexyl-N-methyl-aminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2117] Prepared analogously to Example 231.

[2118] Yield: 44% of theory,

[2119] Melting point: 215° C.

[2120] C₂₉H₃₀N₄O₃ (482.59)

[2121] Mass spectrum: M⁺=482

EXAMPLE 233

[2122](Z)-3-{1-[4-(phenylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2123] Prepared analogously to Example 231.

[2124] Melting point: 274-277° C.

[2125] C₂₈H₂₂N₄O₃ (462.51)

[2126] Mass spectrum: M⁺=462

[2127] Calc.: C, 72.71; H, 4.79; N, 12.11. Found: 72.61; 4.91; 12.09.

EXAMPLE 234

[2128](Z)-3-{1-[4-(N-methyl-N-phenyl-aminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2129] Prepared analogously to Example 231.

[2130] Melting point: 228-230° C.

[2131] C₂₉H₂₄N₄O₃ (476.54)

[2132] Mass spectrum: M⁺=476

[2133] Calc.: C, 73.09; H, 5.08; N, 11.76. Found: 72.79; 5.25; 11.56.

EXAMPLE 235

[2134](Z)-3-{1-[4-(N-methyl-N-(2-pyridyl)-aminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2135] Prepared analogously to Example 231.

[2136] Melting point: 213°-216° C.

[2137] C₂₈H₂₃N₅O₃ (477.53)

[2138] Mass spectrum: M⁺=477

EXAMPLE 236

[2139](Z)-3-{1-[4-(N-benzyl-N-tert.butoxycarbonyl-aminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2140] Prepared analogously to Example 231.

[2141] Melting point: 202-203° C. (decomposition)

[2142] C₃₄H₃₂N₄O₅ (576.66)

[2143] Mass spectrum: M⁺=576

[2144] Calc.: C, 70.82; H, 5.59; N, 9.72. Found: 70.81; H, 5.74; N, 9.65

EXAMPLE 237

[2145](Z)-3-{1-[4-(benzylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone-hydrochloride

[2146] Prepared analogously to Examples 236 and 29a.

[2147] Melting point: 298-300° C.

[2148] C₂₉H₂₄N₄O₃ (476.534)

[2149] Mass spectrum: M⁺=476

[2150] C₂₉H₂₄N₄O₃ x HCl x 1.5H₂O (540.02)

[2151] Calc.: C, 64.50; H, 5.23; N, 10.37. Found: 64.79; 5.08; 10.38.

EXAMPLE 238

[2152](Z)-3-{1-[4-(N-benzyl-N-methyl-aminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2153] Prepared analogously to Example 231.

[2154] Melting point: 200-201° C.

[2155] C₃₀H₂₆N₄O₃ (490.57)

[2156] Mass spectrum: M⁺=490

[2157] Calc.: C, 73.45; H, 5.34; N, 11.42. Found: 73.25; 5.50; 11.32.

EXAMPLE 239

[2158](Z)-3-{1-[4-(2-hydroxy-ethylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2159] Prepared analogously to Example 231.

[2160] Melting point: 196-198° C.

[2161] C₂₄H₂₂N₄O₄ (430.47)

[2162] Mass spectrum: M⁺ 430

[2163] Calc.: C, 66.97; H, 5.15; N, 13.02. Found: 66.67; 5.35; 12.80.

EXAMPLE 240

[2164](Z)-3-{1-[4-(Bis-(2-hydroxyethyl)-aminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2165] Prepared analogously to Example 231.

[2166] Melting point: 196-198° C.

[2167] C₂₆H₂₆N₄O₅ (474.52)

[2168] Mass spectrum: M⁺=474

[2169] Calc.: C, 65.81; H, 5.52; N, 11.81. Found: 65.53; 5.53; 11.69.

EXAMPLE 241

[2170](Z)-3-{1-[4-(2-ethoxycarbonyl-ethylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2171] Prepared analogously to Example 231.

[2172] Melting point: 129-131° C.

[2173] C₂₇H₂₆N₄O₅ (486.53)

[2174] Mass spectrum: M⁺=486

[2175] Calc.: C, 66.66; H, 5.39; N, 11.52. Found: 66.68; 5.42; 11.50.

EXAMPLE 242

[2176](Z)-3-{1-[4-(2-carboxy-ethylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2177] Prepared analogously to Example 241 and 8.

[2178] Melting point: 220-222° C.

[2179] C₂₅H₂₂N₄O₅ (458.47)

[2180] Mass spectrum: M⁺=458

EXAMPLE 243

[2181](Z)-3-{1-[4-(2-dimethylaminocarbonyl-ethylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2182] Prepared analogously to Example 242 and 18.

[2183] Melting point: 215-217° C.

[2184] C₂₇H₂₇N₅O₄ (485.54)

[2185] Mass spectrum: M⁺=485

EXAMPLE 244

[2186](Z)-3-{1-[4-(4-tert.butoxycarbonyl-piperazin-1-ylmethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2187] Prepared analogously to Example 231.

[2188] Melting point: 236-237° C. (decomposition)

[2189] C₃₁H₃₃N₅O₅ (555.64)

[2190] Mass spectrum: M⁺=555

[2191] Calc.: C, 67.01; H, 5.99; N, 12.60. Found: 66.89; 6.08; 12.65.

EXAMPLE 245

[2192](Z)-3-{1-[4-(piperazin-1-ylmethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone-dihydrochloride

[2193] Prepared analogously to Example 244 and 29a.

[2194] Melting point: >370° C.; sintering from 240° C.

[2195] C₂₆H₂₅N₅O₃ (455.52)

[2196] Mass spectrum: M⁺=455

[2197] C₂₆H₂₅N₅O₃ x 2HCl x 2H₂O (564.47)

[2198] Calc.: C, 55.32; H, 5.54; N, 12.41. Found: 54.96; 5.66; 12.26.

EXAMPLE 246

[2199](Z)-3-{1-[4-(4-acetylpiperazin-1-ylmethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2200] Prepared analogously to Example 245 and 1a.

[2201] Melting point: 275-277° C.

[2202] C₂₈H₂₇N₅O₄ (497.56)

[2203] Mass spectrum: M⁺=497

[2204] C₂₈H₂₇N₅O₄ x 0.5H₂O (506.56)

[2205] Calc.: C, 66.39; H, 5.57; N, 13.83. Found: 66.51; 5.66; 13.70.

EXAMPLE 247

[2206](Z)-3-{1-[4-(4-aminocarbonyl-piperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2207] Prepared analogously to Example 177 and 20.

[2208] Melting point: 296-297° C.

[2209] C₂₈H₂₇N₅O₄ (497.56)

[2210] Mass spectrum: M⁺=497

[2211] C₂₈H₂₇N₅O₄ x 1.5H₂O (524.58)

[2212] Calc.: C, 64.11; H, 5.76; N, 13.35. Found: 64.33; 5.32; 13.19.

EXAMPLE 248

[2213](Z)-3-{1-[4-(4-methylaminocarbonyl-piperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2214] Prepared analogously to Example 177 and 18.

[2215] Melting point: 263-265° C.

[2216] C₂₉H₂₉N₅O₄ (511.59)

[2217] Mass spectrum: M⁺=511

[2218] Calc.: C, 68.09; H, 5.71; N, 13.69. Found: 67.94; 5.78; 13.53.

EXAMPLE 249

[2219](Z)-3-{1-[4-(4-dimethylaminocarbonyl-piperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2220] Prepared analogously to Example 177 and 18.

[2221] Melting point: 272-273° C.

[2222] C₃₀H₃₁N₅O₄ (525.61)

[2223] Mass spectrum: M⁺=525

[2224] C₃₀H₃₁N₅O₄ x 0.5H₂O (534.61)

[2225] Calc.: C, 67.40; H, 6.03; N, 13.10. Found: 67.52; 6.00; 13.15.

EXAMPLE 250

[2226](Z)-3-{1-[4-(4-hydroxymethyl-piperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2227] Prepared analogously to Example 231.

[2228] Melting point: 227-228° C.

[2229] C₂₈H₂₈N₄O₄ (484.56)

[2230] Mass spectrum: M⁺=484

[2231] C₂₈H₂₈N₄O₄ x 0.5H₂O (493.56)

[2232] Calc.: C, 68.14; H, 5.92; N, 11.35. Found: 68.25; 5.94; 11.18.

EXAMPLE 251

[2233](Z)-3-{1-[4-(4-hydroxy-4-methyl-piperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2234] Prepared analogously to Example 231.

[2235] Melting point: 186-187° C.

[2236] C₂₈H₂₈N₄O₄ (484.56)

[2237] Mass spectrum: M⁺=484

[2238] C₂₈H₂₈N₄O₄ x 0.5H₂O (493.56)

[2239] Calc.: C, 68.14; H, 5.92; N, 11.35. Found: 67.87; 6.00; 11.27.

EXAMPLE 252

[2240](Z)-3-{1-[3-(2-carboxyethylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2241] Prepared analogously to Example 112 and 8.

[2242] Melting point: 247-249° C.

[2243] C₂₅H₂₂N₄O₅ (458.47)

[2244] Mass spectrum: M⁺=458

[2245] C₂₅H₂₂N₄O₅ x 1.5H₂O (485.50)

[2246] Calc.: C, 61.85; H, 5.19; N, 11.54. Found: 61.80; 5.16; 11.46.

EXAMPLE 253

[2247](Z)-3-{1-[3-(2-dimethylaminocarbonyl-ethylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2248] Prepared analogously to Example 253 and 18.

[2249] Melting point: 177-179° C.

[2250] C₂₇H₂₇N₅O₄ (485.54)

[2251] Mass spectrum: M⁺=485

[2252] C₂₇H₂₇N₅O₄ x 0.5H₂O (494.55)

[2253] Calc.: C, 65.57; H, 5.71; N, 14.16. Found: 65.43; 5.61; 13.83.

EXAMPLE 254

[2254](Z)-3-{1-[4-(2-methylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2255] a) 4-(2-methylamino-ethyl)-nitrobenzene

[2256] 2.7 g (86 mmol) of methylamine are dissolved in 120 ml ofdichloromethane while cooling with ice. 4.9 g (21 mmol) of4-(2-bromoethyl)-nitrobenzene are added and the mixture is allowed tocome up slowly to ambient temperature. After 15 hours stirring thesolvent is eliminated in vacuo and the residue taken up in water. Anacid pH is created using 2 N hydrochloric acid and the mixture is washedwith dichloromethane. The aqueous phase is then adjusted to a basic pHusing 4 N sodium hydroxide solution and the product is extracted withdichloromethane.

[2257] Yield: 3.1 g (82% of theory)

[2258] b) 4-(2-methylamino-ethyl)-aniline

[2259] Prepared by catalytic hydrogenation of4-(2-methylamino-ethyl)-nitrobenzene over palladium-charcoal in methanolanalogously to Example 39c.

[2260] Yield: 96% of theory

[2261] c)(Z)-3-{1-[4-(2-methylamino-ethyl)-phenylamino]-1-phenyl-methylidene]-5-nitro-2-indolinone

[2262] Prepared analogously to Example 89 by reacting3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(2-methylamino-ethyl)-aniline.

[2263] Yield: 12% of theory

[2264] Melting point: 250-252° C.

[2265] C₂₄H₂₂N₄O₃ (414.46)

[2266] Mass spectrum: M⁺=414

EXAMPLE 255

[2267](Z)-3-{1-[4-(2-ethylamino-ethyl)-phenylamino]-1-phenyl-methylidene]-5-nitro-2-indolinone

[2268] Prepared analogously to Example 254.

[2269] Melting point: 235-237° C.

[2270] C₂₅H₂₄N₄O₃ (428.49)

[2271] Mass spectrum: M⁺=428

[2272] Calc.: C, 70.08; H, 5.65; N, 13.07. Found: 69.73; 5.72; 12.92.

EXAMPLE 256

[2273](Z)-3-{1-[4-(2-(2-hydroxyethylamino)-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2274] Prepared analogously to Example 254.

[2275] Melting point: 236-238° C.

[2276] C₂₅H₂₄N₄O₄ (444.49)

[2277] Mass spectrum: M⁺=444

[2278] C₂₅H₂₄N₄O₄ x 1.5H₂O (471.51)

[2279] Calc.: C, 63.68; H, 5.77; N, 11.88. Found: 63.77; 5.82; 11.60.

EXAMPLE 257

[2280](Z)-3-{1-[4-(2-(2-methoxyethylamino)-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone-hydrobromide

[2281] Prepared analogously to Example 254.

[2282] Melting point: 297-299° C.

[2283] C₂₆H₂₆N₄O₄ (458.52)

[2284] Mass spectrum: M⁺=458

EXAMPLE 258

[2285](Z)-3-{1-[4-(2-carboxymethylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2286] Prepared analogously to Example 178 and 8.

[2287] Melting point: 242-243° C. (decomposition)

[2288] C₂₅H₂₂N₄O₅ (458.48)

[2289] Mass spectrum: (M+H)⁺=459

[2290] C₂₅H₂₂N₄O₅ x 0.5H₂O (467.48)

[2291] Calc.: C, 64.23; H, 4.96; N, 11.98. Found: 64.09; 5.00; 11.87.

EXAMPLE 259

[2292](Z)-3-{1-[4-(2-(4-methylpiperidino)-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2293] Prepared analogously to Example 254.

[2294] Melting point: 252-253° C.

[2295] C₂₉H₃₀N₄O₃ (482.58)

[2296] Mass spectrum: M⁺=483

EXAMPLE 260

[2297](Z)-3-{1-[4-(2-(4-hydroxypiperidino)-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2298] Prepared analogously to Example 254.

[2299] Melting point: 274-276° C.

[2300] C₂₈H₂₈N₄O₄ (484.55)

[2301] Mass spectrum: [M+H]⁺=485

EXAMPLE 261

[2302](Z)-3-{1-[4-(2-(4-methoxypiperidino)-ethyl)-phenylamino]-1-phenyl-methylidene1-5-nitro-2-indolinone

[2303] Prepared analogously to Example 254.

[2304] Melting point: 212-214° C.

[2305] C₂₉H₃₀N₄O₄ (498.58)

[2306] Mass spectrum: [M+H]⁺=499

EXAMPLE 262

[2307](Z)-3-{1-[4-(2-(4-ethoxycarbonyl-piperidino)-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2308] Prepared analogously to Example 254.

[2309] Melting point: 208-213° C.

[2310] C₃₁H₃₂N₄O₅ (540.62)

[2311] Mass spectrum: [M+H]⁺=541

EXAMPLE 263

[2312](Z)-3-{1-[4-(2-(4-carboxypiperidino)-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2313] Prepared analogously to Example 262 and 8.

[2314] Melting point: 287-288° C.

[2315] C₂₉H₂₈N₄O₅ (512.56)

[2316] Mass spectrum: [M+H]⁺=513

EXAMPLE 264

[2317](Z)-3-{1-[4-(2-(4-dimethylaminocarbonyl-piperidino)-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2318] Prepared analogously to Example 263 and 18.

[2319] Melting point: 288° C. (decomposition)

[2320] C₃₁H₃₃N₅O₄ (539.63)

[2321] Mass spectrum: [M+H]⁺=540

EXAMPLE 265

[2322](Z)-3-{1-[4-(2-hexamethyleneimino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2323] Prepared analogously to Example 254.

[2324] Melting point: 217-222° C.

[2325] C₂₉H₃₀N₄O₃ (482.58)

[2326] Mass spectrum: [M+H]⁺=483

EXAMPLE 266

[2327](Z)-3-{1-[4-(dimethylaminomethyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2328] Prepared analogously to Example 1.

[2329] Melting point: 237-240° C.

[2330] C₂₄H₂₃N₃O (369.47)

[2331] Mass spectrum: [M+H]⁺=370

EXAMPLE 267

[2332](Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2333] Prepared analogously to Example 1.

[2334] Melting point: 235-240° C.

[2335] C₂₇H₂₇N₃O (409.53)

[2336] Mass spectrum: [M+H]⁺=410

EXAMPLE 268

[2337](Z)-3-{1-[4-(2-dimethylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2338] Prepared analogously to Example 1 and 254.

[2339] Melting point: 244-246° C.

[2340] C₂₅H₂₅N₃O (383.49)

[2341] Mass spectrum: [M+H]⁺=384

EXAMPLE 269

[2342](Z)-3-{1-[4-(2-(3,6-Dihydro-2H-pyridin-1-yl)-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2343] a) 4-[2-(3,6-Dihydro-2H-pyridin-1-yl)-ethyl]-aniline

[2344] 2.5 g (11.1 mmol) of tin dichloride dihydrate are added atambient temperature to a solution of 1.5 g (6.46 mmol) of4-[2-(3,6-dihydro-2H-pyridin-1-yl)-ethyl]-nitrobenzene, preparedanalogously to Example 254, in 7 ml of glacial acetic acid and 2.5 ml ofconcentrated hydrochloric acid. The mixture is heated for 4 hours to100° C., then another 2.5 g (11.1 mmol) of tin dichloride dihydrate areadded and the mixture is heated for 12 hours to 100° C. After coolingthe solvent is eliminated in vacuo and the residue taken up in water.The mixture is made alkaline with 4N sodium hydroxide solution andextracted with dichloromethane. After removal of the solvent in vacuothe product is obtained as an oil.

[2345] Yield: 1.14 g (88% of theory)

[2346] C₁₃H₁₈N₂ (202.3)

[2347] Mass spectrum: [M+H]⁺=203

[2348] b)(Z)-3-{1-[4-(2-(3,6-Dihydro-2H-pyridin-1-yl)-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2349] Prepared analogously to Example 89 by reacting3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-[2-(3,6-dihydro-2H-pyridin-1-yl)-ethyl]-aniline.

[2350] Yield: 88% of theory

[2351] Melting point: 249-254° C. (decomposition)

[2352] C₂₈H₂₆N₄O₃ (466.54)

[2353] Mass spectrum: [M+H]⁺=467

EXAMPLE 270

[2354](Z)-3-{1-[4-(3,6-Dihydro-2H-pyridin-1-ylmethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2355] Prepared analogously to Example 269.

[2356] Melting point: 222-225° C.

[2357] C₂₇H₂₄N₄O₃ (452.51)

[2358] Mass spectrum: M⁺=452

EXAMPLE 271

[2359](Z)-3-{1-[4-(pyrimidin-2-ylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2360] a) 4-(pyrimidin-2-ylaminomethyl)-nitrobenzene

[2361] 9.4 g (50 mmol) of 4-nitrobenzylamine-hydrochloride, 11.7 g (110mmol) of sodium carbonate and 7.5 g (50 mmol) of sodium iodide are addedto a solution of 5.7 g (50 mmol) of 2-chloropyrimidine in 250 ml ofethanol. The mixture is refluxed for 20 hours. Then the salts areremoved by suction filtering, the filtrate is evaporated down and takenup in 300 ml of ethyl acetate. It is washed with water, the solvent iseliminated in vacuo and the residue is chromatographed on silica gel(dichloromethane/methanol=97:3).

[2362] Yield: 2.4 g (21% of theory),

[2363] Melting point: 157-158° C.

[2364] C₁₁H₁₀N₄O₂ (230.23)

[2365] Mass spectrum: [M+H]⁺=231

[2366] b) 4-(pyrimidin-2-ylaminomethyl)-aniline

[2367] Prepared analogously to Example 55 by catalytic hydrogenation of4-(pyrimidin-2-ylaminomethyl)-nitrobenzene with Raney nickel.

[2368] Yield: 89% of theory,

[2369] Melting point: 145-146° C.

[2370] C₁₁H₁₂N₄ (200.25)

[2371] Mass spectrum: [M+H]⁺=201

[2372] c)(Z)-3-{1-[4-(pyrimidin-2-ylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2373] Prepared analogously to Example 89 by reacting3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone with4-(pyrimidin-2-ylaminomethyl)-aniline.

[2374] Yield: 80% of theory,

[2375] Melting point: 284°-286° C.

[2376] C₂₆H₂₀N₆O₃ (464.49)

[2377] Mass spectrum: M⁺=464

[2378] Calc.: C, 67.23; H, 4.34; N, 18.09. Found: 66.86; 4.42; 17.85.

EXAMPLE 272

[2379](Z)-3-{1-[4-((N-methyl-N-pyrimidin-2-yl-amino)-methyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2380] Prepared analogously to Example 271.

[2381] Melting point: 236°-239° C.

[2382] C₂₇H₂₂N₆O₃ (478.51)

[2383] Mass spectrum: M⁺=478

EXAMPLE 273

[2384](Z)-3-{1-[4-(Azetidin-1-yl-methyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2385] a) 4-(Azetidin-1-yl-methyl)-nitrobenzene

[2386] 6.2 g (41 mmol) of 4-nitrobenzaldehyde and 3.8 g (40.6 mmol) ofazetidine-hydrochloride are dissolved in 120 ml of ethanol. 2.6 g (41mmol) of sodium cyanoborohydride are added at 0° C. The mixture isslowly heated to ambient temperature and then stirred for 18 hours. Thenthe solvent is eliminated in vacuo, the residue is taken up in ethylacetate and washed with water. The solvent is eliminated in vacuo andafter chromatography of the residue on silica gel (ethylacetate/methanol/NH₄OH=95:5:0.5) a light brown oil is obtained.

[2387] Yield: 0.9 g (11% of theory),

[2388] C₁₀H₁₂N₂O₂ (192.22)

[2389] Mass spectrum: [M+H]⁺=193

[2390] b) 4-(Azetidin-1-yl-methyl)-aniline

[2391] Prepared analogously to Example 55 by catalytic hydrogenation of4-(azetidin-1-yl-methyl)-nitrobenzene with Raney nickel as a light brownoil.

[2392] Yield: 94% of theory,

[2393] C₁₀H₁₄N₂ (162.24)

[2394] Mass spectrum: [M+H]⁺=163

[2395] c)(Z)-3-{1-[4-(Azetidin-1-yl-methyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2396] Prepared analogously to Example 89 by reacting3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone with4-(azetidin-1-yl-methyl)-aniline.

[2397] Yield: 84% of theory,

[2398] Melting point: 228-229° C.

[2399] C₂₅H₂₂N₄O₃ (426.48)

[2400] Mass spectrum: M⁺=426

EXAMPLE 274

[2401](Z)-3-{1-[4-(cyclopropylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2402] Prepared analogously to Example 273.

[2403] Melting point: 220-221° C. (decomposition)

[2404] C₂₅H₂₂N₄O₃ (426.48)

[2405] Mass spectrum: M⁺=426

EXAMPLE 275

[2406](Z)-3-{1-[4-((N-cyclopropyl-N-methyl-amino)-methyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2407] Prepared analogously to Example 273.

[2408] Melting point: 216-217° C.

[2409] C₂₆H₂₄N₄O₃ (440.51)

[2410] Mass spectrum: M⁺=440

[2411] Calc.: C, 70.89; H, 5.49; N, 12.72. Found: 70.42; 5.52; 12.48.

EXAMPLE 276

[2412](Z)-3-{1-[4-(cyclopentylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2413] Prepared analogously to Example 273.

[2414] Melting point: 231° C.

[2415] C₂₇H₂₆N₄O₃ (454.53)

[2416] Mass spectrum: M⁺=454

[2417] C₂₇H₂₆N₄O₃ x H₂O (472.55)

[2418] Calc.: C, 68.63; H, 5.97; N, 11.86. Found: 68.93; 6.12; 11.62.

EXAMPLE 277

[2419](Z)-3-{1-[4-(N-cyclopentyl-N-methyl-aminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2420] Prepared analogously to Example 273.

[2421] Melting point: 228° C.

[2422] C₂₈H₂₈N₄O₃ (468.56)

[2423] Mass spectrum: M⁺=468

[2424] C₂₈H₂₈N₄O₃ x 1.5H₂O (495.58)

[2425] Calc.: C, 67.86; H, 6.30; N, 11.31. Found: 68.35; 6.42; 11.16.

EXAMPLE 278

[2426](Z)-3-{1-[4-(cyclohexylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2427] Prepared analogously to Example 273.

[2428] Melting point: 245° C.

[2429] C₂₈H₂₈N₄O₃ (468.55)

[2430] Mass spectrum: M⁺=468

[2431] C₂₈H₂₈N₄O₃ x 0.5H₂O (477.56)

[2432] Calc.: C, 70.42; H, 16.12; N, 11.73. Found: 70.60; 6.20; 11.83.

EXAMPLE 279

[2433](Z)-3-{1-[4-(pyridine-2-ylaminomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2434] Prepared analogously to Example 273.

[2435] Melting point: 266-268° C.

[2436] C₂₇H₂₁N₅O₃ (463.49)

[2437] Mass spectrum: M⁺=463

[2438] Calc.: C, 69.97; H, 4.57; N, 15.11. Found: 69.76; 4.62; 14.87.

EXAMPLE 280

[2439](Z)-3-{1-[4-(3-dimethylaminoprop-1-ynyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2440] a) 4-(3-hydroxyprop-1-ynyl)-nitrobenzene

[2441] 8.55 g (0.15 mol) of propargyl alcohol and 152 ml (110 g, 1.09mol) of triethylamine are added to a solution of 20.2 g (0.1 mol) of4-bromonitrobenzene in 285 ml of acetonitrile. The reaction solution isheated to 100° C. 11.9 g (10 mmol) of Pd(Pph₃)₄ and 3.94 g (20 mmol) ofcopper (I) iodide are added. After 10 minutes the solvent is eliminatedin vacuo and the residue taken up in ethyl acetate. It is washed withwater and ammonia water, filtered through Celite and the solvent iseliminated in vacuo. The product is obtained by chromatography on silicagel (dichloromethane/methanol=10:1).

[2442] Yield: 5.95 g (34% of theory)

[2443] Melting point: 98-105° C.

[2444] C₉H₇NO₃ (177.2)

[2445] Mass spectrum: [M−H]⁻=176

[2446] b) 4-[3-(p-Tolylsulphonyloxy)-prop-1-ynyl]-nitrobenzene

[2447] 4.4 ml (54 mmol) of pyridine are added dropwise to a solution of5.8 g (33 mmol) of 4-(3-hydroxyprop-1-ynyl)-nitrobenzene and 5.2 g (27mmol) of p-toluenesulphonic acid chloride in 50 ml of dichloromethane at0° C. After 2 hours at 0° C. about 25 g of ice and 8 ml of conc.hydrochloric acid are added. The organic phase is separated off andwashed with water. After removal of the solvent in vacuo andchromatography of the residue on silica gel(dichloromethane/methanol=1:1) the product is obtained as an oil.

[2448] Yield: 0.7 g (8% of theory)

[2449] C₁₆H₁₃NO₅S (331.3)

[2450] Mass spectrum: M⁺=331

[2451] c) 4-(3-dimethylaminoprop-1-ynyl)-nitrobenzene

[2452] 190 ml (4.2 mmol) of dimethylamine dissolved in 2.5 ml ofdichloromethane are added dropwise at 0° C. to a solution of 0.7 g (2.1mmol) of 4-[3-(p-tolylsulphonyloxy)-prop-1-ynyl]-nitrobenzene in 10 mlof dichloromethane. The cooling is stopped and the mixture is stirredfor 18 hours at ambient temperature. Then the reaction solution iswashed with water and freed from solvent. The residue is chromatographedon silica gel (dichloromethane/methanol=10:1). The product is obtainedas an oil.

[2453] Yield: 278 mg (65% of theory)

[2454] C₁₁H₁₂N₂O₂ (204.2)

[2455] Mass spectrum: [M+H]⁺=205

[2456] d) 4-(3-dimethylaminoprop-1-ynyl)-aniline

[2457] The reaction of 4-(3-dimethylaminoprop-1-ynyl)-nitrobenzene withtin dichloride analogously to Example 269 yields the following threeproducts: 4-(3-dimethylaminoprop-1-ynyl)-aniline

[2458] C₁₁H₁₄N₂ (174.2)

[2459] Mass spectrum: M⁺=174

[2460] (Z)-4-(3-dimethylamino-2-chloroprop-1-enyl)-aniline

[2461] C₁₁H₁₅ClN₂ (210.7)

[2462] Mass spectrum: M⁺=212/210

[2463] (E)-4-(3-dimethylaminoprop-1-enyl)-aniline

[2464] C₁₁H₁₆N₂ (176.2)

[2465] Mass spectrum: M⁺=176

[2466] e)(Z)-3-{1-[4-(3-dimethylaminoprop-1-ynyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2467] Prepared analogously to Example 89 by reacting3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone with4-(3-dimethylaminoprop-1-ynyl)-aniline.

[2468] Yield: 22% of theory

[2469] C₂₆H₂₂N₄O₃ (438.48)

[2470] Mass spectrum: [M+H]⁺=439.5

[2471] R_(f) value: 0.54 (silica gel; dichloromethane/methanol=5:1)

EXAMPLE 281

[2472](Z)-3-{1-[(Z)-4-(3-dimethylamino-2-chloroprop-1-enyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2473] Prepared analogously to Example 280.

[2474] C₂₆H₂₃ClN₄O₃ (474.95)

[2475] Mass spectrum: [M+H]⁺=477/475

[2476] R_(f) value: 0.48 (silica gel; dichloromethane/methanol=5:1)

EXAMPLE 282

[2477](Z)-3-{1-[(E)-4-(3-dimethylaminoprop-1-enyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2478] Prepared analogously to Example 280.

[2479] C₂₆H₂₄N₄O₃ (440.50)

[2480] Mass spectrum: M⁺=440

[2481] R_(f) value: 0.51 (silica gel; dichloromethane/methanol 5:1)

EXAMPLE 283

[2482](Z)-3-{1-[4-(3-dimethylamino-propyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2483] a) 4-(3-dimethylaminopropyl)-aniline

[2484] Prepared by catalytic hydrogenation of4-(3-dimethylaminoprop-1-ynyl)-nitrobenzene (Example 280) analogously toExample 39c.

[2485] C₁₁H₁₈N₂ (178.3)

[2486] Mass spectrum: M⁺=178

[2487] b)(Z)-3-{1-[4-(3-dimethylaminopropyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2488] Prepared analogously to Example 89 by reacting3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone with4-(3-dimethylaminopropyl)-aniline.

[2489] Yield: 35% of theory

[2490] Melting point: 269° C. (decomposition)

[2491] C₂₆H₂₆N₄O₃ (442.52)

[2492] Mass spectrum: M⁺=442

EXAMPLE 284

[2493](Z)-3-{1-[4-(2-dimethylaminoethyloxy)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2494] a) 4-(2-Bromoethyloxy)-nitrobenzene

[2495] 18 g (161 mmol) of potassium tert.butoxide are added to asolution of 20.8 g (150 mmol) of 4-nitrophenol in 100 ml ofdimethylformamide. The temperature of the reaction solution meanwhile ismaintained at <50° C. After 30 minutes the reaction solution is addeddropwise to a solution of 113 g (602 mmol) of 1,2-dibromoethane in 50 mlof dimethylformamide. Then it is heated to 80° C. for 18 hours. Thesolvent is then eliminated in vacuo, the residue taken up indichloromethane, washed with dilute sodium hydroxide solution, dried andevaporated to dryness. The oily residue is chromatographed on silica gel(dichloromethane/cyclohexane=6:4)

[2496] Yield: 13 g (35% of theory)

[2497] Melting point: 66° C.

[2498] R_(f) value: 0.53 (silica gel; dichloromethane/cyclohexane=6:4)

[2499] b) 4-(2-dimethylaminoethyloxy)-nitrobenzene

[2500] 4.9 g (20 mmol) of 4-(2-bromoethyloxy)-nitrobenzene and 2.7 g (60mmol) of dimethylamine in 50 ml of dimethylformamide are heated to 100°C. for 24 hours in a bomb tube. After removal of the solvent in vacuothe residue is taken up in water and extracted with dichloromethane. Theorganic phase is dried and concentrated by evaporation.

[2501] Yield: 2.9 g (69% of theory)

[2502] C₁₀H₁₄N₂O₃ (210.224)

[2503] Mass spectrum: [M+H]⁺=211

[2504] R_(f) value: 0.45 (silica gel; dichloromethane/ethanol=9:1)

[2505] c) 4-(2-dimethylaminoethyloxy)-aniline

[2506] Prepared by catalytic hydrogenation of4-(2-dimethylaminoethyloxy)-nitrobenzene analogously to Example 39

[2507] Yield: 93% of theory

[2508] C₁₀H₁₆N₂O (180.25)

[2509] Mass spectrum: [M+H]⁺=181

[2510] d)(Z)-3-{1-[4-(2-dimethylaminoethyloxy)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2511] Prepared analogously to Example 11 by reacting3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone with4-(2-dimethylaminoethyloxy)-aniline.

[2512] Yield: 35% of theory

[2513] Melting point: 258-260° C.

[2514] C₂₅H₂₅N₃O₂ (399.49)

[2515] Mass spectrum: M⁺=399

[2516] Calc.: C, 76.79; H, 6.89; N, 9.26. Found: 76.43; 6.83; 9.20.

EXAMPLE 285

[2517](Z)-3-{1-[4-(2-piperidinoethyloxy)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2518] Prepared analogously to Example 284.

[2519] Melting point: 198-200° C.

[2520] C₂₈H₂₉N₃O₂ (439.56)

[2521] Mass spectrum: M⁺=439

EXAMPLE 286

[2522](Z)-3-{1-[4-(3-dimethylaminopropyloxy)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2523] Prepared analogously to Example 284.

[2524] Melting point: 215-217° C.

[2525] C₂₆H₂₇N₃O₂ (413.52)

[2526] Mass spectrum: M⁺=413

EXAMPLE 287

[2527](Z)-3-{1-[4-(3-piperidinopropyloxy)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2528] Prepared analogously to Example 284.

[2529] Melting point: 223-225° C.

[2530] C₂₉H₃₁N₃O₂ (453.58)

[2531] Mass spectrum: M⁺=453

EXAMPLE 288

[2532](Z)-3-{1-[4-(3-(N-benzyl-N-methyl-amino)-propyloxy)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2533] Prepared analogously to Example 284.

[2534] Melting point: 187-189° C.

[2535] C₃₂H₃₁N₃O₂ (489.62)

[2536] Mass spectrum: M⁺=489

EXAMPLE 289

[2537](Z)-3-{1-[4-(ethyloxycarbonylmethyloxy)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2538] Prepared analogously to Example 284.

[2539] Melting point: 175-177° C.

[2540] C₂₅H₂₂N₂O₄ (414.46)

[2541] Mass spectrum: M⁺=414

EXAMPLE 290

[2542](Z)-3-{1-[4-(carboxymethyloxy)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2543] Prepared analogously to Example 289 and 8.

[2544] Melting point: 238-240° C.

[2545] C₂₃H₁₈N₂O₄ (386.41)

[2546] Mass spectrum: M⁺=386

EXAMPLE 291

[2547](Z)-3-{1-[4-(dimethylaminocarbonylmethyloxy)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2548] Prepared analogously to Example 290 and 18.

[2549] Melting point: 224-226° C.

[2550] C₂₅H₂₃N₃O₃ (413.47)

[2551] Mass spectrum: M⁺=413

EXAMPLE 292

[2552](Z)-3-1-[4-(N-(2-dimethylamino-ethylaminocarbonylmethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2553] Prepared analogously to Example 192.

[2554] Melting point: 145° C.

[2555] C₂₈H₃₀N₆O₆S (578.65)

[2556] Mass spectrum: M⁺=578

[2557] C₂₈H₃₀N₆O₆S x 1.5H₂O (605.67)

[2558] Calc.: C, 55.53; H, 5.49; N, 13.88. Found: 55.54; 5.59; 13.68.

EXAMPLE 293

[2559](Z)-3-{1-[4-(N-((N-(2-dimethylaminoethyl)-N-methyl-amino)-carbonylmethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2560] Prepared analogously to Example 192.

[2561] Melting point: 170° C.

[2562] C₂₉H₃₃N₅O₄S (547.68)

[2563] Mass spectrum: M⁺=547

[2564] Calc: C, 63.60; H, 6.07; N, 12.79. Found: 63.38; 6.12; 12.67.

EXAMPLE 294

[2565](Z)-3-{1-[4-(N-((N-(2-dimethylaminoethyl)-N-methyl-amino)-carbonylmethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2566] Prepared analogously to Example 192.

[2567] Melting point: 138-140° C.

[2568] C₂₉H₃₂N₆O₆S (592.67)

[2569] Mass spectrum: M⁺=592

[2570] C₂₉H₃₂N₆O₆S x H₂O (601.68)

[2571] Calc: C, 57.89; H, 5.53; N, 13.97. Found: 57.58; 5.57; 13.84.

EXAMPLE 295

[2572](Z)-3-{1-[4-(N-(2-dimethylamino-ethylaminocarbonylmethyl)-N-ethylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2573] Prepared analogously to Example 192.

[2574] Melting point: 155° C.

[2575] C₂₉H₃₂N₆O₆S (592.67)

[2576] Mass spectrum: M⁺=592

[2577] C₂₉H₃₂N₆O₆S x H₂O (610.69)

[2578] Calc: C, 57.04; H, 5.61; N, 13.76. Found: 56.96; 5.63; 13.73.

EXAMPLE 296

[2579](Z)-3-{1-[4-(N-((N-(2-dimethylaminoethyl)-N-methyl-amino)-carbonylmethyl)-N-ethylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2580] Prepared analogously to Example 192.

[2581] Melting point: 117° C.

[2582] C₃₀H₃₄N₆O₆S (606.70)

[2583] Mass spectrum: M⁺=606

[2584] Calc: C, 59.39; H, 5.65; N, 13.85. Found: 59.29; 5.78; 13.65.

EXAMPLE 297

[2585](Z)-3-{1-[4-(N-ethoxycarbonylmethyl-N-ethylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2586] Prepared analogously to Example 198.

[2587] Melting point: 228-230° C.

[2588] C₂₇H₂₇N₃O₅S (505.59)

[2589] Mass spectrum: M⁺=505

[2590] C₂₇H₂₇N₃O₅S x 0.5H₂O (514.60)

[2591] Calc.: C, 63.02; H, 5.48; N, 8.17. Found: 62.70; 5.37; 8.29.

EXAMPLE 298

[2592](Z)-3-{1-[4-(N-carboxymethyl-N-ethylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2593] Prepared analogously to Example 297 and 8.

[2594] Melting point: 240-242° C.

[2595] C₂₅H₂₃N₃O₅S (477.54)

[2596] Mass spectrum: M⁺=477

[2597] R_(f) value: 0.3 (silica gel; dichloromethane/methanol=9:1)

EXAMPLE 299

[2598](Z)-3-{1-[4-(N-aminocarbonylmethyl-N-ethylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2599] Prepared analogously to Example 298 and 20.

[2600] Melting point: 259° C.

[2601] C₂₅H₂₄N₄O₄S (476.55)

[2602] Mass spectrum: M⁺=476

[2603] C₂₅H₂₄N₄O₄S x 0.3H₂O (481.96)

[2604] Calc: C, 62.30; H, 15.14; N, 11.62. Found: 62.50; 5.31; 11.55.

EXAMPLE 300

[2605](Z)-3-1′-[4-(N-methylaminocarbonylmethyl-N-ethylsulphonyl-amino-phenylamino1-phenyl-methylidene}-2-indolinone

[2606] Prepared analogously to Example 298 and 18.

[2607] Melting point: 242° C.

[2608] C₂₆H₂₆N₄O₄S (490.58)

[2609] Mass spectrum: M⁺=490

EXAMPLE 301

[2610](Z)-3-{1-[4-(N-(2-dimethylamino-ethylaminocarbonylmethyl)-N-ethylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2611] Prepared analogously to Example 298 and 18.

[2612] Melting point: 203° C.

[2613] C₂₉H₃₃N₅O₄S (547.68)

[2614] Mass spectrum: M⁺=547

EXAMPLE 302

[2615](Z)-3-{1-[4-(N-((N-(2-dimethylaminoethyl)-N-methyl-amino)-carbonylmethyl)-N-ethylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2616] Prepared analogously to Example 298 and 18.

[2617] Melting point: 170-172° C.

[2618] C₃₀H₃₅N₅O₄S (561.70)

[2619] Mass spectrum: M⁺=561

EXAMPLE 303

[2620](Z)-3-{1-[4-(N-(dimethylaminocarbonylmethyl)-N-benzylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2621] Prepared analogously to Example 187.

[2622] Melting point: 159-161° C.

[2623] C₃₂H₂₉N₅O₆S (611.68)

[2624] Mass spectrum: M⁺=611

EXAMPLE 304

[2625](Z)-3-{1-[4-(N-(dimethylaminocarbonylmethyl)-N-isopropylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2626] Prepared analogously to Example 187.

[2627] Melting point: 146-148° C.

[2628] C₂₈H₃₀N₄O₄S (518.63)

[2629] Mass spectrum: M⁺=518

[2630] Calc.: C, 64.84; H, 5.83; N, 10.80. Found: 65.11; 5.82; 10.67.

EXAMPLE 305

[2631](Z)-3-{1-[4-(N-(dimethylaminocarbonylmethyl)-N-propylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2632] Prepared analogously to Example 187.

[2633] Melting point: 178-180° C.

[2634] C₂₈H₃₀N₄O₄S (518.63)

[2635] Mass spectrum: M⁺=518

EXAMPLE 306

[2636](Z)-3-{1-[4-(N-(dimethylaminocarbonylmethyl)-N-butylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2637] Prepared analogously to Example 187.

[2638] Melting point: 121-123° C.

[2639] C₂₉H₃₂N₄O₄S (532.66)

[2640] Mass spectrum: M⁺=532

[2641] C₂₉H₃₂N₄O₄S x 2H₂O (568.69)

[2642] Calc.: C, 61.25; H, 6.38; N, 9.85. Found: 61.59; 6.49; 10.00.

EXAMPLE 307

[2643](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-ethylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2644] Prepared analogously to Example 187.

[2645] Melting point: 245° C.

[2646] C₂₇H₃₀N₄O₃S (490.63)

[2647] Mass spectrum: M⁺=490

[2648] C₂₇H₃₀N₄O₃S x 0.2H₂O (494.22)

[2649] Calc: C, 65.62; H, 6.20; N, 11.34. Found: 65.72; 6.33; 11.27.

EXAMPLE 308

[2650](Z)-3-{1-[4-(N-(2-morpholinoethyl)-N-ethylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2651] Prepared analogously to Example 187.

[2652] Melting point: 222-224° C.

[2653] C₂₉H₃₂N₄O₄S (532.66)

[2654] Mass spectrum: M⁺=532

EXAMPLE 309

[2655](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-isopropylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2656] a) isopropylsulphonicacid-(4-tert.butoxycarbonylamino-phenyl)-amide

[2657] 1.2 g (10 mmol) of isopropylsulphonic acid chloride are addeddropwise to a solution of 1.0 g (4.8 mmol) of4-tert.butoxycarbonylamino-aniline in 10 ml of pyridine. The mixture isstirred for 18 hours at ambient temperature. Then the reaction solutionis poured onto 150 ml of ice water and then extracted with ethylacetate. The organic phases are washed with water and freed fromsolvent. The residue is chromatographed on silica gel(dichloromethane/methanol/NH₄OH=19:1:0.1).

[2658] Yield: 0.8 g (53% of theory)

[2659] C₁₄H₂₂N₂O₄S (314.41)

[2660] Mass spectrum: [M−H]⁻=313

[2661] b) 4-isopropylsulphonylamino-aniline

[2662] Prepared analogously to Example 29a from isopropylsulphonicacid-(4-tert.butoxycarbonylamino-phenyl)-amide.

[2663] C₉H₁₄N₂O₂S (214.28)

[2664] Mass spectrum: M⁺=214

[2665] c)(Z)-1-acetyl-3-[-(4-isopropylsulphonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone

[2666] Prepared analogously to Example 1c from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-isopropylsulphonylamino-aniline.

[2667] Yield: 27% of theory

[2668] Melting point: 258° C.

[2669] C₂₆H₂₅N₃O₄S (475.57)

[2670] Mass spectrum: [M−H]⁻=474

[2671] d)(Z)-3-{-[4-(N-(2-dimethylaminoethyl)-N-isopropylsulphonyl-amino]-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2672] Prepared analogously to Example 36 from(Z)-3-{1-[4-(isopropylsulphonylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinone,1-chloro-2-dimethylamino-ethane, potassium carbonate and sodium iodidein acetone.

[2673] Yield: 14% of theory

[2674] Melting point: 247° C.

[2675] C₂₈H₃₂N₄O₃S (504.65)

[2676] Mass spectrum: [M+H]⁺=505

[2677] C₂₈H₃₂N₄O₃S x 0.2H₂O (508.25)

[2678] Calc.: C, 66.17; H, 6.43; N, 11.02. Found: 66.19; 6.40; 10.78.

EXAMPLE 310

[2679](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-propylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2680] Prepared analogously to Example 187.

[2681] Melting point: 212° C.

[2682] C₂₈H₃₁N₅O₅S (549.65)

[2683] Mass spectrum: M⁺=549

EXAMPLE 311

[2684](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-propylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2685] Prepared analogously to Example 187.

[2686] Melting point: 245° C.

[2687] C₂₈H₃₂N₄O₃S (504.65)

[2688] Mass spectrum: M⁺=504

[2689] Calc: C, 66.64; H, 6.39; N, 11.10. Found: 66.40; 6.44; 11.00.

EXAMPLE 312

[2690](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-phenylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2691] Prepared analogously to Example 187.

[2692] Melting point: 241-243° C.

[2693] C₃₁H₃₀N₄O₃S (538.67)

[2694] Mass spectrum: M⁺=538

EXAMPLE 313

[2695](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-benzylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2696] Prepared analogously to Example 187.

[2697] Melting point: 248° C.

[2698] C₃₂H₃₁N₅O₅S (597.69)

[2699] Mass spectrum: M⁺=597

EXAMPLE 314

[2700](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-benzylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2701] Prepared analogously to Example 187.

[2702] Melting point: 244° C.

[2703] C₃₂H₃₂N₄O₃S (552.70)

[2704] Mass spectrum: M⁺=552

[2705] C₃₂H₃₂N₄O₃S x 0.5H₂O (560.69)

[2706] Calc: C, 68.55; H, 5.75; N, 9.99. Found: 68.99; 5.99; 9.83.

EXAMPLE 315

[2707](Z)-3-{1-[4-(N-(3-dimethylaminopropyl)-N-methylsulphonyl-amino-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2708] Prepared analogously to Example 187.

[2709] Melting point: 227° C.

[2710] C₂₇H₃₀N₄O₃S (490.63)

[2711] Mass spectrum: [M+H]⁺=491

[2712] Calc.: C, 66.10; H, 6.16; N, 11.42. Found: 66.04; 6.14; 11.43.

EXAMPLE 316

[2713](Z)-3-{1-[4-(N-(3-dimethylaminopropyl)-N-ethylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2714] Prepared analogously to Example 187.

[2715] Melting point: 194° C.

[2716] C₂₈H₃₂N₄O₃S (504.65)

[2717] Mass spectrum: [M+H]⁺=505

[2718] Calc.: C, 66.64; H, 6.39; N, 11.10. Found: 66.43; 6.37; 10.88.

EXAMPLE 317

[2719](Z)-3-{1-[3-(N-ethoxycarbonylmethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2720] Prepared analogously to Example 187.

[2721] Melting point: 188-190° C.

[2722] C₂₆H₂₅N₃O₅S (491.57)

[2723] Mass spectrum: M⁺=491

[2724] Calc.: C, 63.53; H, 5.13; N, 8.55. Found: 63.67; 5.20; 8.59.

EXAMPLE 318

[2725](Z)-3-{1-[3-(N-carboxymethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2726] Prepared analogously to Example 317 and 8.

[2727] Melting point: 270° C. (decomposition)

[2728] C₂₄H₂₁N₃O₅S (463.51)

[2729] Mass spectrum: [M−H]⁻=462

EXAMPLE 319

[2730](Z)-3-{1-[3-(N-aminocarbonylmethyl-N-methylsulphonyl-amino)-phenylamino-1-phenyl-methylidene}-2-indolinone

[2731] Prepared analogously to Example 318 and 20.

[2732] Melting point: 227-230° C.

[2733] C₂₄H₂₂N₄O₄S (462.53)

[2734] Mass spectrum: M⁺=462

EXAMPLE 320

[2735](Z)-3-1-[3-(N-methylaminocarbonylmethyl-N-methylsulphonyl-amino]-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2736] Prepared analogously to Example 318 and 20.

[2737] Melting point: 163° C.

[2738] C₂₅H₂₄N₄O₄S (476.55)

[2739] Mass spectrum: M⁺=476

EXAMPLE 321

[2740](Z)-3-{1′-[3-(N-dimethylaminocarbonylmethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2741] Prepared analogously to Example 318 and 20.

[2742] Melting point: 213-216° C.

[2743] C₂₆H₂₆N₄O₄S (490.58)

[2744] Mass spectrum: M⁺=490

EXAMPLE 322

[2745](Z)-3-{1-[3-(N-(2-dimethylamino-ethylaminocarbonylmethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2746] Prepared analogously to Example 318 and 18.

[2747] Melting point: 179-181° C.

[2748] C₂₈H₃₁N₅O₄S (533.65)

[2749] Mass spectrum: M⁺=533

EXAMPLE 323

[2750](Z)-3-{1-[3-(N-((N-(2-dimethylaminoethyl)-N-methyl-amino)-carbonylmethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2751] Prepared analogously to Example 318 and 18.

[2752] Melting point: 197-199° C.

[2753] C₂₉H₃₃N₅O₄S (547.68)

[2754] Mass spectrum: M⁺=547

[2755] Calc.: C, 63.60; H, 6.07; N, 12.79; S, 5.85. Found: 63.52; 6.14;12.72; 5.85.

EXAMPLE 324

[2756](Z)-3-{1-[3-(N-(2-dimethylaminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2757] Prepared analogously to Example 187.

[2758] Melting point: 208-211° C.

[2759] C₂₆H₂₈N₄O₃S (476.60)

[2760] Mass spectrum: M⁺=476

[2761] Calc.: C, 65.52; H, 5.92; N, 11.76. Found: 65.22; 5.84; 11.64.

EXAMPLE 325

[2762](Z)-3-{1-[3-(N-(2-morpholinoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2763] Prepared analogously to Example 187.

[2764] Melting point: 177-179° C.

[2765] C₂₈H₃₀N₄O₄S (518.63)

[2766] Mass spectrum: M⁺=518

EXAMPLE 326

[2767](Z)-3-{1-[4-(2-dimethylamino-ethylamino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2768] a) 4-(2-dimethylamino-ethylamino)-nitrobenzene

[2769] 2.2 ml of (20 mmol) of 4-fluoronitrobenzene and 2.6 ml (24 mmol)of N,N-dimethylethylene-diamine are heated in 10 ml of ethanol at 120°C. in a microwave oven for 1.5 hours. Then 50 ml of 1 N hydrochloricacid are added. The reaction solution is washed with ethyl acetate. Thenthe aqueous phase is combined with 4 N sodium hydroxide solution untilan alkaline reaction is obtained and extracted with ethyl acetate. Thecombined organic phases are washed with water, dried over magnesiumsulphate and freed from solvent. The product is obtained as a yellowoil.

[2770] Yield: 11.7 g (61% of theory)

[2771] C₁₀H₁₅N₃O₂ (209.25)

[2772] Mass spectrum: [M+H]⁺=210

[2773] b) 4-(2-dimethylamino-ethylamino)-aniline

[2774] Prepared analogously to Example 39c by catalytic hydrogenation of4-(2-dimethylamino-ethylamino)-nitrobenzene.

[2775] Yield: 94% of theory

[2776] C₁₀H₁₇N₃ (179.27)

[2777] Mass spectrum: [M+H]⁺=180

[2778] c)(Z)-3-{1-[4-(2-dimethylamino-ethylamino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2779] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(2-dimethylamino-ethylamino)-aniline.

[2780] Yield: 25% of theory

[2781] Melting point: 227-229° C.

[2782] C₂₅H₂₅N₅O₃ (443.50)

[2783] Mass spectrum: M⁺=443

[2784] C₂₅H₂₅N₅O₃ x 0.5H₂O (452.51)

[2785] Calc.: C, 66.36; H, 5.79; N, 15.48. Found: 66.25; 5.60; 15.52.

EXAMPLE 327

[2786](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-formyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2787] a) 4-(N-(2-dimethylaminoethyl)-N-formyl-amino)-nitrobenzene

[2788] 1.4 g (6.7 mmol) of 4-(2-dimethylamino-ethylamino)-nitrobenzene(Example 326a) are refluxed for 4 hours in 20 ml of formic acid. Thenthe solvent is eliminated in vacuo, the residue taken up in water andcombined with 2 N sodium hydroxide solution until an alkaline reactionis obtained. The mixture is extracted with ethyl acetate, the combinedorganic phases are dried over magnesium sulphate and the solvent iseliminated in vacuo. The product is obtained as an oil.

[2789] Yield: 1.3 g (78% of theory)

[2790] C₁₁H₁₅N₃O₃ (237.26)

[2791] Mass spectrum: [M+H]⁺=238

[2792] b) 4-(N-(2-dimethylaminoethyl)-N-formyl-amino)-aniline

[2793] Prepared analogously to Example 39c by catalytic hydrogenation of4-(N-(2-dimethylaminoethyl)-N-formyl-amino)-nitrobenzene.

[2794] Yield: 82% of theory

[2795] C₁₁H₁₇N₃O (207.28)

[2796] Mass spectrum: M⁺=207

[2797] c)(Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-formyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2798] Prepared analogously to Example 89 from3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and4-(N-(2-dimethylaminoethyl)-N-formyl-amino)-aniline.

[2799] Yield: 47% of theory

[2800] Melting point: 215-218° C.

[2801] C₂₆H₂₅N₅O₄ (471.51)

[2802] Mass spectrum: M⁺=471

EXAMPLE 328

[2803](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-acetyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2804] Prepared analogously to Example 327.

[2805] Melting point: 228-230° C.

[2806] C₂₇H₂₇N₅O₄ (485.54)

[2807] Mass spectrum: [M+H]⁺=486

EXAMPLE 329

[2808](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-propionyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2809] Prepared analogously to Example 327.

[2810] Melting point: 263-265° C.

[2811] C₂₈H₂₉N₅O₄ (499.57)

[2812] Mass spectrum: M⁺=499

[2813] Calc.: C, 67.32; H, 5.85; N, 14.02. Found: 67.16; 6.00; 13.81.

EXAMPLE 330

[2814](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-isopropylcarbonyl-amino]-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2815] Prepared analogously to Example 327.

[2816] Melting point: 296-298° C.

[2817] C₂₉H₃₁N₅O₄ (513.59)

[2818] Mass spectrum: M⁺=513

[2819] Calc.: C, 67.82; H, 6.08; N, 13.64. Found: 67.53; 6.29; 13.51.

EXAMPLE 331

[2820](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-propylcarbonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2821] Prepared analogously to Example 327.

[2822] Melting point: 275-277° C.

[2823] C₂₉H₃₁N₅O₄ (513.59)

[2824] Mass spectrum: M⁺=513

[2825] Calc.: C, 67.82; H, 6.08; N, 13.64. Found: 67.71; 6.31; 13.54.

EXAMPLE 332

[2826](Z)-3-{1-[4-(2-morpholinoethylamino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2827] Prepared analogously to Example 326.

[2828] Melting point: 253° C.

[2829] C₂₇H₂₇N₅O₄ (485.54)

[2830] Mass spectrum: M⁺=485

[2831] C₂₇H₂₇N₅O₄ x 0.5H₂O (494.54)

[2832] Calc.: C, 65.57; H, 5.71; N, 14.16. Found: 65.58; 5.70; 14.08.

EXAMPLE 333

[2833](Z)-3-{1-[4-(N-(2-morpholinoethyl)-N-formyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2834] Prepared analogously to Example 327.

[2835] Melting point: 207° C.

[2836] C₂₈H₂₇N₅O₅ (513.55)

[2837] Mass spectrum: M⁺=513

[2838] Calc: C, 65.49; H, 5.30; N, 13.64. Found: 65.19; 5.30; 13.51.

EXAMPLE 334

[2839](Z)-3-{1-[4-(N-(2-morpholinoethyl)-N-acetyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2840] 486 mg (1.0 mmol) of(Z)-3-{1-[4-(2-morpholinoethylamino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone(Example 332) are dissolved in 30 ml of dichloromethane and combinedwith 1.2 ml (16 mmol) of acetylchloride. The mixture is stirred for 1hour at ambient temperature. The precipitate is removed by suctionfiltering and the reaction solution is washed with water. Then thesolvent is eliminated in vacuo, the residue is dissolved in 20 ml ofmethanol and combined with 4 ml of 1 N sodium hydroxide solution. Themixture is stirred for 30 minutes at ambient temperature and then thesolvent is eliminated in vacuo. The residue is suspended in water and alittle ether. Then the product is suction filtered and dried.

[2841] Yield: 35% of theory

[2842] Melting point: 229° C.

[2843] C₂₉H₂₉N₅O₅ (527.58)

[2844] Mass spectrum: M⁺=527

[2845] C₂₉H₂₉N₅O₅ x 0.5H₂O (536.59)

[2846] Calc: C, 64.91; H, 5.64; N, 13.05. Found: 65.29; 5.62; 12.98.

EXAMPLE 335

[2847](Z)-3-{1′-[4-(N-(2-morpholinoethyl)-N-propionyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2848] Prepared analogously to Example 327.

[2849] Melting point: 232° C.

[2850] C₃₀H₃₁N₅O₅ (541.60)

[2851] Calc: C, 66.53; H, 5.77; N, 12.93. Found: 66.60; 5.99; 12.65.

EXAMPLE 336

[2852](Z)-3-{1-[4-(N-(2-morpholinoethyl)-N-isopropylcarbonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2853] Prepared analogously to Example 327.

[2854] Melting point: 254° C.

[2855] C₃₁H₃₃N₅O₅ (555.63)

[2856] Mass spectrum: M⁺=555

[2857] Calc: C, 67.01; H, 5.99; N, 12.60. Found: 66.80; 6.01; 12.54.

EXAMPLE 337

[2858](Z)-3-{1-[4-(N-(2-morpholinoethyl)-N-propylcarbonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[2859] Prepared analogously to Example 327.

[2860] Melting point: 228° C.

[2861] C₃₁H₃₃N₅O₅ (555.63)

[2862] Mass spectrum: M⁺=555

[2863] Calc: C, 67.01; H, 5.99; N, 12.60. Found: 66.85; 6.00; 12.52.

EXAMPLE 338

[2864](Z)-3-{1-[4-(2-dimethylamino-ethylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2865] Prepared analogously to Example 326.

[2866] Melting point: 258-260° C.

[2867] C₂₅H₂₆N₄O (398.51)

[2868] Mass spectrum: M⁺=398

EXAMPLE 339

[2869](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-formyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2870] Prepared analogously to Example 327.

[2871] Melting point: 246-248° C.

[2872] C₂₆H₂₆N₄O₂ (426.52)

[2873] Mass spectrum: M⁺=426

EXAMPLE 340

[2874](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-acetyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2875] Prepared analogously to Example 327.

[2876] Melting point: 197-199° C.

[2877] C₂₇H₂₈N₄O₂ (440.54)

[2878] Mass spectrum: M⁺=440

EXAMPLE 341

[2879](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-propionyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2880] Prepared analogously to Example 327.

[2881] Melting point: 272-274° C.

[2882] C₂₈H₃₀N₄O₂ (454.57)

[2883] Mass spectrum: M⁺=454

[2884] Calc.: C, 73.98; H, 6.65; N, 12.33. Found: 73.71; 6.79; 12.32.

EXAMPLE 342

[2885](Z)-3-{1′-[4-(N-(2-dimethylaminoethyl)-N-isopropylcarbonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2886] Prepared analogously to Example 327.

[2887] Melting point: 280-282° C.

[2888] C₂₉H₃₂N₄O₂ (468.60)

[2889] Mass spectrum: M⁺=468

[2890] C₂₉H₃₂N₄O₂ x 0.5H₂O (477.61)

[2891] Calc.: C, 72.93; H, 6.96; N, 11.73. Found: 72.71; 6.86; 11.87.

EXAMPLE 343

[2892](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-propylcarbonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2893] Prepared analogously to Example 327.

[2894] Melting point: 268-270° C.

[2895] C₂₉H₃₂N₄O₂ (468.60)

[2896] Mass spectrum: M⁺=468

[2897] Calc.: C, 74.33; H, 6.88; N, 11.96. Found: 74.27; 6.95; 11.97.

EXAMPLE 344

[2898](Z)-3-{1-[4-(N-(3-dimethylaminopropyl)-N-acetyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2899] Prepared analogously to Example 327.

[2900] Melting point: 227° C.

[2901] C₂₈H₃₀N₄O₂ (454.57)

[2902] Mass spectrum: M⁺=454

[2903] Calc.: C, 73.98; H, 6.65; N, 12.33. Found: 73.62; 6.61; 12.13.

EXAMPLE 345

[2904](Z)-3-{1-[4-(N-(3-dimethylaminopropyl)-N-propionyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2905] Prepared analogously to Example 327.

[2906] Melting point: 224° C.

[2907] C₂₉H₃₂N₄O₂ (468.60)

[2908] Mass spectrum: M⁺=468

[2909] C₂₉H₃₂N₄O₂ x 0.5H₂O (477.61)

[2910] Calc.: C, 72.93; H, 6.96; N, 11.73. Found: 72.99; 6.85; 11.63.

EXAMPLE 346

[2911](Z)-3-{1-[4-(2-morpholinoethylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2912] Prepared analogously to Example 326.

[2913] Melting point: 257° C.

[2914] C₂₇H₂₈N₄O₂ (440.54)

[2915] Mass spectrum: M⁺=440

[2916] Calc: C, 73.61; H, 6.41; N, 12.72. Found: 73.57; 6.48; 12.62.

EXAMPLE 347

[2917](Z)-3-{1-[4-(N-(2-morpholinoethyl)-N-formyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2918] Prepared analogously to Example 327.

[2919] Melting point: 218° C.

[2920] C₂₈H₂₈N₄O₃ (468.55)

[2921] Mass spectrum: M⁺=468

EXAMPLE 348

[2922](Z)-3-{1-[4-(N-(2-morpholinoethyl)-N-acetyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2923] Prepared analogously to Example 334.

[2924] Melting point: from 90° C. (sintering)

[2925] C₂₉H₃₀N₄O₃ (482.58)

[2926] Mass spectrum: M⁺=482

EXAMPLE 349

[2927](Z)-3-{1′-[4-(N-(2-morpholinoethyl)-N-propionyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2928] Prepared analogously to Example 334.

[2929] Melting point: 228° C.

[2930] C₃₀H₃₂N₄O₃ (496.61)

[2931] Mass spectrum: M⁺=496

[2932] C₃₀H₃₂N₄O₃ x 0.3H₂O (502.01)

[2933] Calc.: C, 71.78; H, 16.55; N, 11.16. Found: 71.70; 6.56; 11.13.

EXAMPLE 350

[2934](Z)-3-{1-[4-(N-(2-morpholinoethyl)-N-isopropylcarbonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2935] Prepared analogously to Example 327.

[2936] Melting point: 239° C.

[2937] C₃₁H₃₄N₄O₃ (510.63)

[2938] Mass spectrum: M⁺=510

EXAMPLE 351

[2939](Z)-3-{1-[4-(N-(2-morpholinoethyl)-N-propylcarbonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2940] Prepared analogously to Example 327.

[2941] Melting point: 219° C.

[2942] C₃₁H₃₄N₄O₃ (510.63)

[2943] Mass spectrum: M⁺=510

[2944] C₃₁H₃₄N₄O₃ x 0.3H₂O (516.04)

[2945] Calc.: C, 72.15; H, 6.76; N, 10.86. Found: 72.10; 6.66; 10.79.

EXAMPLE 352

[2946](Z)-3-{1-[4-(N-ethoxycarbonylmethyl-N-acetyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2947] Prepared analogously to Example 187.

[2948] Melting point: 244-247° C.

[2949] C₂₇H₂₅N₃O₄ (455.51)

[2950] Mass spectrum: M⁺=455

[2951] Calc.: C, 71.19; H, 5.53; N, 9.22. Found: 71.01; 5.59; 9.36.

EXAMPLE 353

[2952](Z)-3-{1-[4-(N-carboxymethyl-N-acetyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2953] Prepared analogously to Example 352 and 8.

[2954] Melting point: 276° C. (decomposition)

[2955] C₂₅H₂₁N₃O₄ (427.46)

[2956] Mass spectrum: M⁺=427

[2957] C₂₅H₂₁N₃O₄ x 0.3H₂O (432.86)

[2958] Calc.: C, 69.37; H, 5.03; N, 9.71. Found: 69.41; 5.16; 9.70.

EXAMPLE 354

[2959](Z)-3-{1-[4-(N-methylaminocarbonylmethyl-N-acetyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2960] Prepared analogously to Example 353 and 18.

[2961] Melting point: 270° C. (decomposition)

[2962] C₂₆H₂₄N₄O₃ (440.50)

[2963] Mass spectrum: M⁺=440

EXAMPLE 355

[2964](Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl-N-acetyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2965] Prepared analogously to Example 353 and 18.

[2966] Melting point: 264-268° C.

[2967] C₂₇H₂₆N₄O₃ (454.53)

[2968] Mass spectrum: M⁺=454

[2969] C₂₇H₂₆N₄O₃ x 0.3H₂O (459.93)

[2970] Calc.: C, 70.51; H, 5.83; N, 12.18. Found: 70.52; 5.86; 12.10.

EXAMPLE 356

[2971](Z)-3-{1-[4-(N-ethoxycarbonylmethyl-N-propionyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2972] Prepared analogously to Example 187.

[2973] Melting point: 229-232° C.

[2974] C₂₈H₂₇N₃O₄ (469.54)

[2975] Mass spectrum: M⁺=469

[2976] Calc.: C, 71.63; H, 5.80; N, 8.95. Found: 71.49; 5.85; 8.92.

EXAMPLE 357

[2977] (Z)-3-{1-[4-(N-carboxymethyl-N-propionyl-amino)-phenylamino]1-phenyl-methylidene}-2-indolinone

[2978] Prepared analogously to Example 356 and 8.

[2979] Melting point: 270° C. (decomposition)

[2980] C₂₆H₂₃N₃O₄ (441.48)

[2981] Mass spectrum: M⁺=441

[2982] Calc.: C, 70.74; H, 5.25; N, 9.52. Found: 70.46; 5.44; 9.39.

EXAMPLE 358

[2983](Z)-3-{1-[4-(N-methylaminocarbonylmethyl-N-propionyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2984] Prepared analogously to Example 357 and 18.

[2985] Melting point: 268° C.

[2986] C₂₇H₂₆N₄O₃ (454.53)

[2987] Mass spectrum: M⁺=454

[2988] C₂₇H₂₆N₄O₃ x 0.5H₂O (463.54)

[2989] Calc.: C, 69.96; H, 5.87; N, 12.09. Found: 69.53; 6.01; 12.17.

EXAMPLE 359

[2990](Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl-N-propionyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2991] Prepared analogously to Example 357 and 18.

[2992] Melting point: 274-277° C.

[2993] C₂₈H₂₈N₄O₃ (468.55)

[2994] Mass spectrum: M⁺=468

[2995] Calc.: C, 71.78; H, 16.02; N, 11.96. Found: 71.70; 6.21; 11.94.

EXAMPLE 360

[2996](Z)-3-{1-[4-(N-ethoxycarbonylmethyl-N-benzoyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[2997] Prepared analogously to Example 187.

[2998] Melting point: 209-211° C.

[2999] C₃₂H₂₇N₃O₄ (517.58)

[3000] Mass spectrum: M⁺=517

EXAMPLE 361

[3001](Z)-3-{1-[4-(N-carboxymethyl-N-benzoyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3002] Prepared analogously to Example 360 and 8.

[3003] Melting point: 277° C. (decomposition)

[3004] C₃₀H₂₃N₃O₄ (489.53)

[3005] Mass spectrum: M⁺=489

EXAMPLE 362

[3006](Z)-3-{1-[4-(N-methylaminocarbonylmethyl-N-benzoyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3007] Prepared analogously to Example 361 and 18.

[3008] Melting point: 260-262° C.

[3009] C₃₁H₂₆N₄O₃ (502.57)

[3010] Mass spectrum: M⁺=502

[3011] Calc.: C, 74.09; H, 5.21; N, 11.15. Found: 74.01; 5.36; 11.09.

EXAMPLE 363

[3012](Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl-N-benzoyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3013] Prepared analogously to Example 361 and 18.

[3014] Melting point: 284-287° C.

[3015] C₃₂H₂₈N₄O₃ (516.60)

[3016] Mass spectrum: M⁺=516

[3017] C₃₂H₂₈N₄O₃ x 0.25H₂O (521.10)

[3018] Calc.: C, 73.76; H, 5.51; N, 10.75. Found: 73.71; 5.67; 10.89.

EXAMPLE 364

[3019](Z)-3-{1-[4-(N-(pyrrolidin-1-ylmethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[3020] Prepared analogously to Example 43.

[3021] Melting point: 246-247° C.

[3022] C₂₈H₂₇N₅O₄ (497.55)

[3023] Mass spectrum: M⁺=497

[3024] Calc.: C, 67.59; H, 5.47; N, 14.08. Found: 67.34; 5.53; 14.00.

EXAMPLE 365

[3025](Z)-3-{1-[4-(N-phthalimidomethylcarbonyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3026] Prepared analogously to Example 43.

[3027] Melting point: 278-280° C.

[3028] C₃₂H₂₄N₄O₄ (528.57)

[3029] Mass spectrum: M⁺=528

EXAMPLE 366

[3030](Z)-3-{1-[4-(N-aminomethylcarbonyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3031] Prepared analogously to Example 365 and 139b.

[3032] Melting point: 238-239° C.

[3033] C₂₄H₂₂N₄O₂ (398.46)

[3034] Mass spectrum: M⁺=398

[3035] C₂₄H₂₂N₄O₂ x 0.5H₂O (407.47)

[3036] Calc.: C, 70.74; H, 5.69; N, 13.75. Found: 70.91; 5.76; 13.73.

EXAMPLE 367

[3037](Z)-3-{1-[4-(N-acetylaminomethylcarbonyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3038] Prepared analogously to Example 366 and 140.

[3039] Melting point: 255-256° C.

[3040] C₂₆H₂₄N₄O₃ (440.50)

[3041] Mass spectrum: [M−H]⁻=439

EXAMPLE 368

[3042](Z)-3-{1-[4-(acetylaminomethylcarbonylamino)-phenylamino]-1-phenyl]-methylidene}-2-indolinone

[3043] Prepared analogously to Example 43.

[3044] Melting point: 245-247° C.

[3045] C₂₅H₂₂N₄O₃ (426.47)

[3046] Mass spectrum: M⁺=426

EXAMPLE 369

[3047](Z)-3-{1-[4-(N-(pyrrolidin-1-ylmethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3048] Prepared analogously to Example 43.

[3049] Melting point: 253-255° C.

[3050] C₂₈H₂₈N₄O₂ (452.56)

[3051] Mass spectrum: M⁺=452

EXAMPLE 370

[3052](Z)-3-{1-[4-(N-(N-benzyl-N-methyl-aminomethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3053] Prepared analogously to Example 43.

[3054] Melting point: 195-197° C.

[3055] C₃₂H₃₀N₄O₂ (502.62)

[3056] Mass spectrum: [M+H]⁺=503

[3057] C₃₂H₃₀N₄O₂ x 0.5H₂O (511.62)

[3058] Calc.: C, 75.12; H, 6.11; N, 10.95. Found: 75.41; 6.00; 10.92.

EXAMPLE 371

[3059](Z)-3-{1-[4-(N-(2-methoxyethylaminomethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3060] Prepared analogously to Example 43.

[3061] Melting point: 186-188° C.

[3062] C₂₇H₂₈N₄O₃ (456.54)

[3063] Mass spectrum: M⁺=456

EXAMPLE 372

[3064](Z)-3-{1-[4-(N-(N-(2-methoxyethyl)-N-methyl-aminomethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3065] Prepared analogously to Example 43.

[3066] Melting point: 197-199° C.

[3067] C₂₈H₃₀N₄O₃ (470.57)

[3068] Mass spectrum: M⁺=470

EXAMPLE 373

[3069](Z)-3-{1-[4-(N-(2-morpholinoethylaminomethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3070] Prepared analogously to Example 43.

[3071] Melting point: 117-119° C.

[3072] C₃₀H₃₃N₅O₃ (511.62)

[3073] Mass spectrum: M⁺=511

EXAMPLE 374

[3074](Z)-3-{1-[4-(N-(N-(2-morpholinoethyl)-N-methyl-aminomethyl-carbonyl)-N-methylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3075] Prepared analogously to Example 43.

[3076] Melting point: 116-118° C.

[3077] C₃₁H₃₅N₅O₃ (525.65)

[3078] Mass spectrum: M⁺=525

EXAMPLE 375

[3079](Z)-3-{1-[4-(N-(N-(2-dimethylaminoethyl)-N-methyl-aminomethylcarbonyl)-N-methylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3080] Prepared analogously to Example 43.

[3081] Melting point: 167-169° C.

[3082] C₂₉H₃₃N₅O₂ (483.61)

[3083] Mass spectrum: M⁺=483

EXAMPLE 376

[3084](Z)-3-{1-[4-(N-(2-tert.butoxycarbonylamino-ethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3085] Prepared analogously to Example 39.

[3086] Melting point: 246-248° C.

[3087] C₃₀H₃₂N₄O₄ (512.61)

[3088] Mass spectrum: M⁺=512

[3089] Calc.: C, 70.29; H, 6.29; N, 10.93. Found: 70.43; 6.15; 11.12.

EXAMPLE 377

[3090](Z)-3-{1-[4-(N-(2-aminoethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone-hydrochloride

[3091] Prepared analogously to Example 376 and 29a.

[3092] Melting point: 97-99° C.

[3093] C₂₅H₂₄N₄O₂ (412.49)

[3094] Mass spectrum: M⁺=412

EXAMPLE 378

[3095](Z)-3-{1-[4-(N-(2-acetylamino-ethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3096] Prepared analogously to Example 376 and 31.

[3097] Melting point: 187-189° C.

[3098] C₂₇H₂₆N₄O₃ (454.53)

[3099] Mass spectrum: M⁺=454

EXAMPLE 379

[3100](Z)-3-{1-[4-(2-dimethylamino-ethylsulphonylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3101] a) 4-(2-dimethylamino-ethylsulphonylamino]-nitrobenzene

[3102] 2.45 g (15 mmol) of 2-chloroethanesulphonic acid chloride areslowly added dropwise at 0° C. to a solution of 1.4 g (10 mmol) ofnitroaniline in 25 ml of pyridine. The mixture is then stirred for 2hours at ambient temperature. After removal of the solvent in vacuo theresidue is combined with water. The precipitate is suction filtered andwashed with water. 3.0 g of1-[2-(4-nitrophenylsulphamoyl)-ethyl]-pyridinium-chloride are obtainedas a crude product. 2.6 g of this crude product are dissolved in 25 mlof DMF and combined with 2 g (20 mmol) of triethylamine and 1.2 g (15mmol) of dimethylamine-hydrochloride. The mixture is stirred for 1.5hours at 100° C., then the reaction solution is poured into water andextracted with ethyl acetate. The organic extracts are dried overmagnesium sulphate and evaporated to dryness.

[3103] Yield: 1.6 g (59% of theory)

[3104] R_(f) value: 0.26 (silica gel;dichloromethane/methanol/NH₄OH=7:3:0.1)

[3105] b) 4-(2-dimethylamino-ethylsulphonylamino)-aniline

[3106] Prepared analogously to Example 39c by catalytic hydrogenation of4-(2-dimethylamino-ethylsulphonylamino)-nitrobenzene.

[3107] Yield: 88% of theory

[3108] R_(f) value: 0.34 (silica gel; dichloromethane/methanol=7:3)

[3109] c)(Z)-3-{1-[4-(2-dimethylamino-ethylsulphonylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3110] Prepared analogously to Example 39 from3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-(2-dimethylamino-ethylsulphonylamino)-aniline.

[3111] Yield: 50% of theory

[3112] Melting point: 214-216° C.

[3113] C₂₅H₂₆N₄O₃S (462.57)

[3114] Mass spectrum: M⁺=462

[3115] Calc.: C, 64.92; H, 5.67; N, 12.11. Found: 64.88; 5.71; 11.98.

EXAMPLE 380

[3116](Z)-3-{1-[4-(2-piperidinoethylsulphonylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3117] Prepared analogously to Example 379.

[3118] Melting point: 225-227° C.

[3119] C₂₈H₃₀N₄O₃S (502.64)

[3120] Mass spectrum: M⁺=502

[3121] Calc.: C, 66.91; H, 6.02; N, 11.15. Found: 67.09; 5.95; 11.10.

EXAMPLE 381

[3122](Z)-3-{1-[4-(2-morpholinoethylsulphonylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3123] Prepared analogously to Example 379.

[3124] Melting point: 240-242° C.

[3125] C₂₇H₂₈N₄O₄S (504.61)

[3126] Mass spectrum: M⁺=504

EXAMPLE 382

[3127](Z)-3-{1-[4-(N-(2-dimethylamino-ethylsulphonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3128] a)4-[N-(2-dimethylamino-ethylsulphonyl)-N-methyl-amino]-nitrobenzene

[3129] 0.49 g (4.4 mmol) of potassium tert.butoxide are added at ambienttemperature to a solution of 1.1 g (4 mmol) of4-(2-dimethylamino-ethylsulphonylamino)-nitrobenzene (Example 379a) in20 ml of DMSO. After 1.5 hours stirring 0.85 g (6 mmol) of methyl iodideare added. The mixture is stirred for 18 hours, then the reactionsolution is poured into water and extracted with ethyl acetate. Thecombined organic phases are dried over magnesium sulphate and thesolvent is eliminated in vacuo. 0.9 g of ethenesulphonicacid-N-(4-nitrophenyl)-N-methyl-amide are obtained as a crude product.0.75 g of this crude product are dissolved in ethanol and combined withan excess of dimethylamine. After 18 hours stirring the mixture isevaporated to dryness.

[3130] Yield: 81% of theory

[3131] R_(f) value: 0.35 (silica gel; dichloromethane/methanol 19:1)

[3132] b) 4-[N-(2-dimethylamino-ethylsulphonyl)-N-methyl-amino]-aniline

[3133] Prepared analogously to Example 39c by catalytic hydrogenation of4-[N-(2-dimethylamino-ethylsulphonyl)-N-methyl-amino]-nitrobenzene.

[3134] Yield: 89% of theory

[3135] R_(f) value: 0.29 (silica gel; dichloromethane/methanol=9:1)

[3136] c)(Z)-3-{1-[4-(N-(2-dimethylamino-ethylsulphonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3137] Prepared analogously to Example 39 from3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-[N-(2-dimethylamino-ethylsulphonyl)-N-methyl-amino]-aniline.

[3138] Yield: 42% of theory

[3139] Melting point: 165-168° C.

[3140] C₂₆H₂₈N₄O₃S (476.60)

[3141] Mass spectrum: [M+H]⁺=476

EXAMPLE 383

[3142](Z)-3-{1-[4-(N-(2-piperidinoethylsulphonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3143] Prepared analogously to Example 382.

[3144] Melting point: 121-123° C.

[3145] C₂₉H₃₂N₄O₃S (516.66)

[3146] Mass spectrum: M⁺=516

EXAMPLE 384

[3147](Z)-3-{1-[4-(N-(2-morpholinoethylsulphonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3148] Prepared analogously to Example 382.

[3149] Melting point: 115-117° C.

[3150] C₂₈H₃₀N₄O₄S (518.63)

[3151] Mass spectrum: M⁺=518

EXAMPLE 385

[3152](Z)-3-{1-[4-(diethylaminocarbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3153] Prepared analogously to Example 18.

[3154] Melting point: 202-204° C.

[3155] C₂₆H₂₅N₃O₂ (411.50)

[3156] Mass spectrum: M⁺=411

EXAMPLE 386

[3157](Z)-3-{1-[4-(pyrrolidin-1-ylcarbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3158] Prepared analogously to Example 18.

[3159] Melting point: 127-129° C.

[3160] C₂₆H₂₃N₃O₂ (409.49)

[3161] Mass spectrum: M⁺=409

EXAMPLE 387

[3162](Z)-3-{1-[4-(piperidinocarbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3163] Prepared analogously to Example 18.

[3164] Melting point: 212-214° C.

[3165] C₂₇H₂₅N₃O₂ (423.51)

[3166] Mass spectrum: M⁺=423

EXAMPLE 388

[3167](Z)-3-{1-[4-(2-methoxyethylaminocarbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3168] Prepared analogously to Example 18.

[3169] Melting point: 277-279° C.

[3170] C₂₅H₂₃N₃O₃ (413.47)

[3171] Mass spectrum: M⁺=413

EXAMPLE 389

[3172](Z)-3-{1-[4-(N-(2-methoxyethyl)-N-methyl-aminocarbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3173] Prepared analogously to Example 18.

[3174] Melting point: 198-200° C.

[3175] C₂₆H₂₅N₃O₃ (427.50)

[3176] Mass spectrum: M⁺=427

[3177] Calc.: C, 73.05; H, 5.89; N, 9.83. Found: 72.75; 6.04; 9.75.

EXAMPLE 390

[3178](Z)-3-{1-[4-(2-dimethylamino-ethylaminocarbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3179] Prepared analogously to Example 18.

[3180] Melting point: 145-147° C.

[3181] C₂₆H₂₆N₄O₂ (426.52)

[3182] Mass spectrum: M⁺=426

EXAMPLE 391

[3183](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-methyl-aminocarbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3184] Prepared analogously to Example 18.

[3185] Melting point: 181-183° C.

[3186] C₂₇H₂₈N₄O₂ (440.54)

[3187] Mass spectrum: M⁺=440

[3188] Calc.: C, 73.61; H, 6.41; N, 12.72. Found: 73.51; 6.59; 12.75.

EXAMPLE 392

[3189](Z)-3-{1-[4-(ethoxycarbonylmethylaminocarbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3190] Prepared analogously to Example 18.

[3191] Melting point: 235-237° C.

[3192] C₂₆H₂₃N₃O₄ (441.48)

[3193] Mass spectrum: M⁺=441

EXAMPLE 393

[3194](Z)-3-{1-[4-(carboxymethylaminocarbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3195] Prepared analogously to Example 392 and 8.

[3196] Melting point: 245-247° C.

[3197] C₂₄H₁₉N₃O₄ (413.43)

[3198] Mass spectrum: M⁺=413

EXAMPLE 394

[3199](Z)-3-{1-[4-(N-ethoxycarbonylmethyl-N-methyl-aminocarbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3200] Prepared analogously to Example 18.

[3201] Melting point: 95-98° C.

[3202] C₂₇H₂₅N₃O₄ (455.51)

[3203] Mass spectrum: M⁺=455

EXAMPLE 395

[3204](Z)-3-{1-[4-(N-carboxymethyl-N-methyl-aminocarbonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3205] Prepared analogously to Example 394 and 8.

[3206] Melting point: 168-170° C.

[3207] C₂₅H₂₁N₃O₄ (427.46)

[3208] Mass spectrum: M⁺=427

EXAMPLE 396

[3209](Z)-3-{1′-[4-(aminosulphonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3210] Prepared analogously to Example 39d.

[3211] Melting point: 254° C.

[3212] C₂₁H₁₇N₃O₃S (391.45)

[3213] Mass spectrum: M⁺=391

[3214] C₂₁H₁₇N₃O₃S x H₂O (409.35)

[3215] Calc.: C, 61.60; H, 4.68; N, 10.26. Found: 61.86; 4.72; 10.27.

EXAMPLE 397

[3216](Z)-3-{1-[4-(pyrrolidin-1-ylsulphonyl)-phenylamino]-11-phenyl-methylidene}-2-indolinone

[3217] a) 4-(pyrrolidin-1-ylsulphonyl)-aniline

[3218] 525 mg (3 mmol) of sulphanilic acid fluoride and 1.07 g (15 mmol)of pyrrolidine are heated together to 80° C. for 15 minutes. Then wateris added to the reaction mixture. The precipitate formed is filtered offand recrystallised from methanol.

[3219] Yield: 375 mg (55% of theory)

[3220] Melting point: 170-172° C.

[3221] R_(f) value: 0.44 (silica gel; dichloromethane/ethyl acetate=9:1)

[3222] b)(Z)-3-{1-[4-(pyrrolidin-1-ylsulphonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3223] Prepared analogously to Example 1c from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-(pyrrolidin-1-ylsulphonyl)-aniline.

[3224] Yield: 45% of theory

[3225] Melting point: 293-294° C.

[3226] C₂₅H₂₃N₃O₃S (445.54)

[3227] Mass spectrum: M⁺=445

[3228] C₂₅H₂₃N₃O₃S x 0.25H₂O (450.04)

[3229] Calc.: C, 66.72; H, 5.26; N, 9.34. Found: 66.62; 5.29; 9.12.

EXAMPLE 398

[3230](Z)-3-{1-[4-(diethylaminosulphonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3231] Prepared analogously to Example 397.

[3232] Melting point: 252-254° C.

[3233] C₂₅H₂₅N₃O₃S (447.56)

[3234] Mass spectrum: M⁺=447

[3235] Calc.: C, 67.09; H, 5.63; N, 9.39. Found: 66.96; 5.68; 9.25.

EXAMPLE 399

[3236](Z)-3-{1-[4-(2-dimethylamino-ethylaminosulphonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3237] Prepared analogously to Example 397.

[3238] Melting point: 233-235° C.

[3239] C₂₅H₂₆N₄O₃S (462.57)

[3240] Mass spectrum: M⁺=462

[3241] C₂₅H₂₆N₄O₃S x 0.25H₂O (467.07)

[3242] Calc.: C, 64.29; H, 5.72; N, 12.00. Found: 64.15; 5.64; 12.00.

EXAMPLE 400

[3243](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-methyl-aminosulphonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3244] Prepared analogously to Example 397.

[3245] Melting point: 200-203° C.

[3246] C₂₆H₂₈N₄O₃S (476.60)

[3247] Mass spectrum: M⁺=476

EXAMPLE 401

[3248](Z)-3-{1-[4-(2-dimethylamino-ethylaminosulphonyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[3249] Prepared analogously to Example 397.

[3250] Melting point: 260-261° C.

[3251] C₂₅H₂₅N₅O₅S (507.57)

[3252] Mass spectrum: M⁺=507

EXAMPLE 402

[3253](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-methyl-aminosulphonyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[3254] Prepared analogously to Example 397.

[3255] Melting point: 215-218° C.

[3256] C₂₆H₂₇N₅O₅S (521.60)

[3257] Mass spectrum: [M+H]⁺=522

[3258] C₂₆H₂₇N₅O₅S x 0.3H₂O (527.00)

[3259] Calc.: C, 59.26; H, 5.28; N, 13.29. Found: 59.25; 5.19; 13.17.

EXAMPLE 403

[3260](Z)-3-{1-[4-(3-dimethylamino-propylaminosulphonyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[3261] Prepared analogously to Example 397.

[3262] Melting point: 268-269° C.

[3263] C₂₆H₂₇N₅O₅S (521.60)

[3264] Mass spectrum: M⁺=521

[3265] Calc.: C, 59.87; H, 5.22; N, 13.43. Found: 59.65; 5.32; 13.26.

EXAMPLE 404

[3266](Z)-3-{1-[4-(N-(3-dimethylaminopropyl)-N-methyl-aminosulphonyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[3267] Prepared analogously to Example 397.

[3268] Melting point: 269-270° C. (decomposition)

[3269] C₂₇H₂₉N₅O₅S (535.62)

[3270] Mass spectrum: M⁺=535

[3271] Calc.: C, 60.55; H, 5.46; N, 13.08. Found: 60.28; 5.56; 12.90.

EXAMPLE 405

[3272](Z)-3-{1-[4-(dimethylaminosulphonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3273] a) 4-nitrobenzenesulphonic acid-dimethylamide

[3274] 4.43 g (20 mmol) of 4-nitrobenzenesulphonic acid chloride areadded dropwise at 0° C. to a solution of 2.45 g (30 mmol) ofdimethylamine-hydrochloride and 6.46 g (50 mmol) ofN,N-diisopropyl-N-methylamine in 30 ml of dichloromethane. The mixtureis stirred for 18 hours at ambient temperature. Then the reactionsolution is washed with water and dilute hydrochloric acid, dried overmagnesium sulphate and evaporated to dryness.

[3275] Yield: 4.4 g (90% of theory)

[3276] b) 4-aminobenzenesulphonic acid-dimethylamide

[3277] Prepared analogously to Example 39c by catalytic hydrogenation of4-nitrobenzenesulphonic acid-dimethylamide.

[3278] Yield: 78% of theory

[3279] Melting point: 172-173° C.

[3280] c)(Z)-3-{1-[4-(dimethylaminosulphonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3281] Prepared analogously to Example 1c from1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and4-aminobenzenesulphonic acid-dimethylamide.

[3282] Yield: 78% of theory

[3283] Melting point: 280° C.

[3284] C₂₃H₂₁N₃O₃S (419.50)

[3285] Mass spectrum: M⁺=419

[3286] Calc.: C, 65.85; H, 5.05; N, 10.02. Found: 65.54; 5.24; 9.96.

EXAMPLE 406

[3287](Z)-3-{1-[4-(ethoxycarbonylmethylaminosulphonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3288] Prepared analogously to Example 405.

[3289] Melting point: 196-199° C.

[3290] C₂₅H₂₃N₃O₅S (477.54)

[3291] Mass spectrum: M⁺=477

[3292] Calc.: C, 62.88; H, 4.85; N, 8.80. Found: 62.79; 5.04; 8.68.

EXAMPLE 407

[3293](Z)-3-{1-[4-(carboxymethylaminosulphonyl)-phenylamino]-1-phenyl-methylidene1-2-indolinone

[3294] Prepared analogously to Example 406 and 8.

[3295] Melting point: 236° C. (decomposition)

[3296] C₂₃H₁₉N₃O₅S (449.49)

[3297] Mass spectrum: M⁺=449

EXAMPLE 408

[3298](Z)-3-{1-[4-(N-ethoxycarbonylmethyl-N-methyl-aminosulphonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3299] Prepared analogously to Example 405.

[3300] Melting point: 178-180° C.

[3301] C₂₆H₂₅N₃O₅S (491.57)

[3302] Mass spectrum: M⁺=491

EXAMPLE 409

[3303](Z)-3-{1-[4-(N-carboxymethyl-N-methyl-aminosulphonyl)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3304] Prepared analogously to Example 408 and 8.

[3305] Melting point: 237° C. (decomposition)

[3306] C₂₄H₂₁N₃O₅S (463.51)

[3307] Mass spectrum: M⁺=463

EXAMPLE 410

[3308](Z)-3-{1-[4-(ethoxycarbonylmethylaminosulphonyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[3309] Prepared analogously to Example 405.

[3310] Melting point: 247-249° C.

[3311] C₂₅H₂₂N₄O₇S (522.54)

[3312] Mass spectrum: M⁺=522

[3313] Calc.: C, 57.47; H, 4.24; N, 10.72. Found: 57.44; 4.22; 10.66.

EXAMPLE 411

[3314](Z)-3-{1-[4-(carboxymethylaminosulphonyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[3315] Prepared analogously to Example 410 and 8.

[3316] Melting point: 177-180° C. (decomposition)

[3317] C₂₃H₁₈N₄O₇S (494.48)

[3318] Mass spectrum: M⁺=494

[3319] C₂₃H₁₈N₄O₇S x H₂O (512.50)

[3320] Calc.: C, 53.90; H, 3.93; N, 10.93. Found: 53.98; 3.95; 10.86.

EXAMPLE 412

[3321](Z)-3-{1-[4-(dimethylaminocarbonylmethylaminosulphonyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[3322] Prepared analogously to Example 411 and 18.

[3323] Melting point: 281-283° C.

[3324] C₂₅H₂₃N₅O₆S (521.55)

[3325] Mass spectrum: M⁺=521

[3326] C₂₅H₂₃N₅O₆S x 0.5H₂O (530.56)

[3327] Calc.: C, 56.60; H, 4.56; N, 13.20. Found: 56.51; 4.56; 13.15.

EXAMPLE 413

[3328](Z)-3-{1-[4-(N-ethoxycarbonylmethyl-N-methyl-aminosulphonyl)-phenyl]amino-1-phenyl-methylidene}-5-nitro-2-indolinone

[3329] Prepared analogously to Example 405.

[3330] Melting point: 206-207° C.

[3331] C₂₆H₂₄N₄O₇S (536.56)

[3332] Mass spectrum: M⁺=536

EXAMPLE 414

[3333](Z)-3-{1-[4-(N-carboxymethyl-N-methyl-aminosulphonyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[3334] Prepared analogously to Example 413 and 8.

[3335] Melting point: 259-260° C.

[3336] C₂₄H₂₀N₄O₇S (508.51)

[3337] Mass spectrum: M⁺=508

EXAMPLE 415

[3338](Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl-N-methyl-aminosulphonyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone

[3339] Prepared analogously to Example 414 and 18.

[3340] Melting point: 277-278° C.

[3341] C₂₆H₂₅N₅O₆S (535.58)

[3342] Mass spectrum: M⁺=535

[3343] Calc.: C, 58.31; H, 4.71; N, 13.08. Found: 58.07; 4.68; 13.03.

EXAMPLE 416

[3344](Z)-3-{1-[3-(N-aminocarbonylmethyl-N-methylsulphonyl-amino)-phenylamino]-1-(4-aminomethyl-phenyl)-methylidene}-2-indolinone

[3345] Prepared analogously to Examples 146, 148 and 191.

[3346] Melting point: 167° C.

[3347] C₂₅H₂₅N₅O₄S (491.57)

[3348] Mass spectrum: [M+H]⁺=492

EXAMPLE 417

[3349](Z)-3-{1-[3-(N-aminocarbonylmethyl-N-methylsulphonyl-amino)-phenylamino]-1-(4-acetylaminomethyl-phenyl)-methylidene}-2-indolinone

[3350] Prepared analogously to Example 416 and 31.

[3351] Melting point: 215° C.

[3352] C₂₇H₂₇N₅O₅S (533.61)

[3353] Mass spectrum: [M−H]⁻=532

EXAMPLE 418

[3354](Z)-3-{1-[3-(N-methylaminocarbonylmethyl-N-methylsulphonyl-amino)-phenylamino]-1-(4-aminomethyl-phenyl)-methylidene}-2-indolinone

[3355] Prepared analogously to Example 146, 148 and 192.

[3356] Melting point: 164° C.

[3357] C₂₆H₂₇N₅O₄S (505.60)

[3358] Mass spectrum: M⁺=505

[3359] C₂₆H₂₇N₅O₄S x 0.7H₂O (518.21)

[3360] Calc.: C, 60.26; H, 5.52; N, 13.51. Found: 60.28; 5.51; 13.78.

EXAMPLE 419

[3361](Z)-3-{1-[3-(N-methylaminocarbonylmethyl-N-methylsulphonyl-amino)-phenylamino]-1-(4-acetylaminomethyl-phenyl)-methylidene}-2-indolinone

[3362] Prepared analogously to Example 418 and 31.

[3363] Melting point: 242° C.

[3364] C₂₈H₂₉N₅O₅S (547.63)

[3365] Mass spectrum: M⁺=547

[3366] C₂₈H₂₉N₅O₅S x 0.5H₂O (556.64)

[3367] Calc.: C, 60.42; H, 5.43; N, 12.58. Found: 60.67; 5.67; 12.30.

EXAMPLE 420

[3368](Z)-3-{-[3-(N-dimethylaminocarbonylmethyl-N-methylsulphonyl-amino)-phenylamino]-1-(4-aminomethyl-phenyl)-methylidene}-2-indolinone

[3369] Prepared analogously to Example 146, 148 and 192.

[3370] Melting point: 220° C.

[3371] C₂₇H₂₉N₅O₄S (519.62)

[3372] Mass spectrum: [M+H]⁺=520

[3373] C₂₇H₂₉N₅O₄S 0.2H₂O (523.23)

[3374] Calc.: C, 61.98; H, 5.66; N, 13.38. Found: 61.95; 5.73; 13.27.

EXAMPLE 421

[3375](Z)-3-1′-[3-(N-dimethylaminocarbonylmethyl-N-methylsulphonyl-amino)-phenylamino]-1-(4-acetylaminomethyl-phenyl)-methylidene}-2-indolinone

[3376] Prepared analogously to Example 420 and 31.

[3377] Melting point: 194° C. (sintering)

[3378] C₂₉H₃₁N₅O₅S (561.66)

[3379] Mass spectrum: [M−H]⁻=560

EXAMPLE 422

[3380](Z)-3-{1-[3-(N-(2-dimethylaminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-(4-aminomethyl-phenyl]-methylidene}-2-indolinone

[3381] Prepared analogously to Example 146, 148 and 324.

[3382] Melting point: 161° C.

[3383] C₂₇H₃₁N₅O₃S (505.64)

[3384] Mass spectrum: M⁺=505

EXAMPLE 423

[3385](Z)-3-{1-[3-(N-(2-dimethylaminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-(4-acetylaminomethyl-phenyl)-methylidene}-2-indolinone

[3386] Prepared analogously to Example 422 and 31.

[3387] Melting point: 180° C.

[3388] C₂₉H₃₃N₅O₄S (547.68)

[3389] Mass spectrum: M⁺=547

EXAMPLE 424

[3390](Z)-3-{1-[3-(N-(3-dimethylaminopropyl)-N-methylsulphonyl-amino)-phenylamino]-1-(4-aminomethyl-phenyl)-methylidene}-2-indolinone

[3391] Prepared analogously to Example 146, 148 and 324.

[3392] Melting point: 197° C.

[3393] C₂₈H₃₃N₅O₃S (519.67)

[3394] Mass spectrum: M⁺=519

[3395] C₂₈H₃₃N₅O₃S 0.5H₂O (528.67)

[3396] Calc.: C, 63.61; H, 6.48; N, 13.25. Found: 63.64; 6.47; 13.39.

EXAMPLE 425

[3397](Z)-3-{1-[3-(N-(3-dimethylaminopropyl)-N-methylsulphonyl-amino)-phenylamino]-1-(4-acetylaminomethyl-phenyl)-methylidene}-2-indolinone

[3398] Prepared analogously to Example 424 and 31.

[3399] Melting point: 208° C.

[3400] C₃₀H₃₅N₅O₄S (561.70)

[3401] Mass spectrum: M⁺=561

[3402] C₃₀H₃₅N₅O₄S 0.8H₂O (576.12)

[3403] Calc.: C, 62.54; H, 6.40; N, 12.16. Found: 62.51; 6.37; 12.13.

EXAMPLE 426

[3404](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-(4-aminomethyl-phenyl)-methylidene}-2-indolinone

[3405] Prepared analogously to Example 146, 148 and 188.

[3406] Melting point: 203-205° C.

[3407] C₂₇H₃₁N₅O₃S (505.64)

[3408] Mass spectrum: M⁺=505

EXAMPLE 427

[3409](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-(4-acetylaminomethyl-phenyl)-methylidene}-2-indolinone

[3410] Prepared analogously to Example 426 and 31.

[3411] Melting point: 225-227° C.

[3412] C₂₉H₃₃N₅O₄S (547.68)

[3413] Mass spectrum: M⁺=547

EXAMPLE 428

[3414](Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl)-N-methylsulphonyl-amino)-phenylamino]-1-(4-aminomethyl-phenyl)-methylidene}-2-indolinone

[3415] Prepared analogously to Example 146, 148 and 193.

[3416] Melting point: 118-120° C.

[3417] C₂₇H₂₉N₅O₄S (519.62)

[3418] Mass spectrum: [M+H]⁺=520

EXAMPLE 429

[3419](Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl)-N-methylsulphonyl-amino)-phenylamino]-1-(4-acetylaminomethyl-phenyl)-methylidene}-2-indolinone

[3420] Prepared analogously to Example 428 and 31.

[3421] Melting point: 147-149° C.

[3422] C₂₉H₃₁N₅O₅S (561.66)

[3423] Mass spectrum: [M−H]⁻=560

EXAMPLE 430

[3424](Z)-3-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-phenylamino]-1-(4-aminomethyl-phenyl)-methylidene}-2-indolinone

[3425] Prepared analogously to Example 146, 148 and 48.

[3426] Melting point: 188-190° C.

[3427] C₂₇H₂₉N₅O₂ (455.56)

[3428] Mass spectrum: M⁺=455

EXAMPLE 431

[3429](Z)-3-{1-[4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-phenylamino]-1-(4-acetylaminomethyl-phenyl)-methylidene}-2-indolinone

[3430] Prepared analogously to Example 430 and 31.

[3431] Melting point: 123-125° C.

[3432] C₂₉H₃₁N₅O₃ (497.60)

[3433] Mass spectrum: M⁺=497

EXAMPLE 432

[3434](Z)-3-[1-(4-piperdinomethyl-phenylamino)-1-(4-bromophenyl)-methylidene]-5-nitro-2-indolinone

[3435] Prepared analogously to Example 146.

[3436] Melting point: 295-297° C.

[3437] C₂₇H₂₅BrN₄O₃ (533.42)

[3438] Mass spectrum: M⁺=534/532

EXAMPLE 433

[3439](Z)-3-[1-(4-piperdinomethyl-phenylamino)-1-(4-iodophenyl)-methylidene]-5-nitro-2-indolinone

[3440] Prepared analogously to Example 146.

[3441] Melting point: 280-283° C.

[3442] C₂₇H₂₅₁N₄O₃ (580.42)

[3443] Mass spectrum: [M+H]⁺=581

EXAMPLE 434

[3444](Z)-3-[1-(4-methoxyphenylamino)-1-(4-iodphenyl)-methylidene]-5-nitro-2-indolinone

[3445] Prepared analogously to Example 146.

[3446] Melting point: 280-283° C.

[3447] C₂₂H₁₆₁N₃O₄ (513.29)

[3448] Mass spectrum: M⁺=513

EXAMPLE 435

[3449](Z)-3-{1-(4-methoxyphenylamino)-1-[(E)-4-(2-methoxycarbonylethenyl)-phenyl]-methylidene}-5-nitro-2-indolinone

[3450] 257 mg (0.5 mmol) of(Z)-3-[1-(4-methoxyphenylamino)-1-(4-iodophenyl)-methylidene]-5-nitro-2-indolinone(Example 434), 0.06 ml (0.75 mmol) of methyl acrylate, 4.5 mg (0.02mmol) of palladium-1′-acetate and 1 ml of (7.2 mmol) of triethylamineare dissolved in 20 ml of acetonitrile under a nitrogen atmosphere. Thesolution is heated for 10 hours to 80° C. Then the reaction solution isfiltered through Celite and the solvent is eliminated in vacuo. Theresidue is chromatographed on silica gel(dichloromethane/methanol=20:1).

[3451] Yield: 0.2 g (85% of theory)

[3452] Melting point: 266-270° C.

[3453] C₂₆H₂₁N₃O₆ (471.47)

[3454] Mass spectrum: M⁺=471

EXAMPLE 436

[3455](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-methylsulphonyl-phenylamino]-1-[4-methoxyphenyl]-methylidene}-2-indolinone

[3456] Prepared analogously to Example 146 and 188.

[3457] Melting point: 219° C.

[3458] C₂₇H₃₀N₄O₄S (506.62)

[3459] Mass spectrum: M⁺=506

[3460] C₂₇H₃₀N₄O₄S x 0.2H₂O (510.23)

[3461] Calc.: C, 63.56; H, 6.01; N, 10.98. Found: 63.61; 6.11; 10.97.

EXAMPLE 437

[3462](Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-methylsulphonyl-phenylamino]-1-[4-chlorophenyl]-methylidene}-2-indolinone

[3463] Prepared analogously to Example 146 and 188.

[3464] Melting point: 263° C.

[3465] C₂₆H₂₇ClN₄O₃S (511.04)

[3466] Mass spectrum: M⁺=512/510

EXAMPLE 438

[3467](Z)-3-{1-[4-Bromophenylamino]-1-[4-(imidazol-1-ylmethyl)-phenyl]-methylidene}-5-nitro-2-indolinone

[3468] Prepared analogously to Example 146.

[3469] Melting point: 260-265° C.

[3470] C₂₅H₁₈BrN₅O₃ (516.35)

[3471] Mass spectrum: M⁺=517/515

EXAMPLE 439

[3472](Z)-3-{1-[4-piperidinomethyl-phenylamino]-1-[4-(imidazol-1-yl-methyl)-phenyl]-methylidene}-5-nitro-2-indolinone

[3473] Prepared analogously to Example 146.

[3474] Melting point: 226-228° C.

[3475] C₃₁H₃₀N₆O₃ (534.62)

[3476] Mass spectrum: M⁺=535

EXAMPLE 440

[3477](Z)-3-{1-[4-(N-benzyl-N-methyl-aminomethyl)-phenylamino]-1-[4-(imidazol-1-ylmethyl)-phenyl]-methylidene}-5-nitro-2-indolinone

[3478] Prepared analogously to Example 146.

[3479] Melting point: 195-198° C.

[3480] C₃₄H₃₀N₆O₃ (570.65)

[3481] Mass spectrum: [M+H]⁺=571

EXAMPLE 441

[3482](Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-(4-methoxyphenyl)-methylidene]-5-nitro-2-indolinone

[3483] a) diethyl [methoxy-(4-methoxyphenyl)-methyl]-phosphonate

[3484] 4.3 ml (35 mmol) of boron trifluoride-etherate are added dropwiseat −20° C. to a solution of 5.6 ml (33 mmol) of anisaldehydedimethylacetal and 5.7 ml (33 mmol) of triethylphosphite in 60 ml ofdichloromethane under a nitrogen atmosphere. The mixture is stirred for18 hours at ambient temperature and then water is added. After 1 hour'sstirring the phases are separated. The organic phase is dried overmagnesium sulphate and the solvent is eliminated in vacuo. The residueis on silica gel chromatographed (dichloromethane/ethyl acetate, 10:1).

[3485] Yield: 7.5 g (79% of theory)

[3486] R_(f) value: 0.5 (silica gel; dichloromethane/ethyl acetate=10:1)

[3487] b)3-[1-methoxy-1-(4-methoxyphenyl)-methylidene]-5-nitro-2-indolinone

[3488] 6.3 g (22 mmol) of diethyl[methoxy-(4-methoxyphenyl)-methyl]-phosphonate are dissolved in 40 ml ofDMF under a nitrogen atmosphere. 5.1 g (45 mmol) of potassiumtert.butoxide are added batchwise at −40° C. and the mixture is thenstirred for another 30 minutes at −10° C. Then 3.84 g (20 mmol) of5-nitroisatine are added. The mixture is stirred for 1 hour at ambienttemperature and then poured onto ice water containing 20 ml of saturatedpotassium hydrogen sulphate solution. The precipitate is suctionfiltered and chromatographed over silica gel(dichloromethane/methanol=10:1).

[3489] Yield: 4.4 g (67% of theory)

[3490] Melting point: 220-225° C.

[3491] C₁₇H₁₄N₂O₅ (326.31)

[3492] Mass spectrum: [M−H]⁻=325

[3493] c)(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-(4-methoxyphenyl)-methylidene]-5-nitro-2-indolinone

[3494] Prepared analogously to Example 39d from3-[1-methoxy-1-(4-methoxyphenyl)-methylidene]-5-nitro-2-indolinone and4-piperidinomethyl-aniline.

[3495] Yield: 90% of theory

[3496] Melting point: 230-233° C.

[3497] C₂₈H₂₈N₄O₄ (484.55)

[3498] Mass spectrum: [M+H]⁺=484

EXAMPLE 442

[3499](Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-(4-trifluoromethyl-phenyl)-methylidene]-5-nitro-2-indolinone

[3500] Prepared analogously to Example 441.

[3501] Melting point: 300-302° C.

[3502] C₂₈H₂₅F₃N₄O₃ (522.52)

[3503] Mass spectrum: M⁺=522

EXAMPLE 443

[3504](Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-(4-chlorophenyl)-methylidene]-5-nitro-2-indolinone

[3505] Prepared analogously to Example 441.

[3506] Melting point: 309-311° C.

[3507] C₂₇H₂₅ClN₄O₃ (488.97)

[3508] Mass spectrum: [M+H]⁺=491/489

EXAMPLE 444

[3509](Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-(4-methoxycarbonyl-phenyl)-methylidene]-5-nitro-2-indolinone

[3510] Prepared analogously to Example 441.

[3511] Melting point: 178-83° C.

[3512] C₂₉H₂₈N₄O₅ (512.56)

[3513] Mass spectrum: M⁺=512

EXAMPLE 445

[3514](Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-(4-carboxyphenyl)-methylidene]-5-nitro-2-indolinone

[3515] Prepared analogously to Example 444 and 8.

[3516] Melting point: 230° C.

[3517] C₂₈H₂₆N₄O₅ (498.54)

[3518] Mass spectrum: [M−H]⁻=497

EXAMPLE 446

[3519](Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-(4-methoxycarbonylmethylaminocarbonyl-phenyl)-methylidene]-5-nitro-2-indolinone

[3520] Prepared analogously to Example 445 and 18.

[3521] Melting point: 230-235° C.

[3522] C₃₁H₃₁N₅O₆ (569.61)

[3523] Mass spectrum: [M+H]⁺=570

EXAMPLE 447

[3524](Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-(4-(2-methoxycarbonyl-ethylaminocarbonyl)-phenyl)-methylidene]-5-nitro-2-indolinone

[3525] Prepared analogously to Example 445 and 18.

[3526] Melting point: 130° C.

[3527] C₃₂H₃₃N₅O₆ (583.64)

[3528] Mass spectrum: M⁺=583

EXAMPLE 448

[3529](Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-6-nitro-2-indolinone

[3530] a) 1-hydroxy-6-nitro-2-indolinone

[3531] 31 g (137 mmol) of 2,4-dinitrophenylacetic acid are dissolved in400 ml of ethyl acetate and hydrogenated over Pd-charcoal analogously toExample 39c.

[3532] Yield: 13.2 g (50% of theory).

[3533] R_(f) value: 0.6 (silica gel; dichloromethane/methanol 9:1)

[3534] C₈H₆N₂O₄ (194.15)

[3535] Mass spectrum: [M−H]⁻=193

[3536] b)1-acetoxy-3-(1-ethoxy-1-phenyl-methylidene)-6-nitro-2-indolinone

[3537] Prepared analogously to Example 1b from1-hydroxy-6-nitro-2-indolinone and triethyl orthobenzoate in aceticanhydride.

[3538] Yield: 62% of theory

[3539] R_(f) value: 0.3 (silica gel; dichloromethane)

[3540] C₁₉H₁₆N₂O₆ (368.35)

[3541] Mass spectrum: [M+Na]⁺=391

[3542] c)(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-1-hydroxy-6-nitro-2-indolinone

[3543] Prepared analogously to Example 1c from1-acetoxy-3-(1-ethoxy-1-phenyl-methylidene)-6-nitro-2-indolinone and4-piperidino-methyl-aniline.

[3544] Yield: 88% of theory

[3545] R_(f) value: 0.48 (silica gel; dichloromethane/methanol=9:1)

[3546] C₂₇H₂₆N₄O₄ (470.53)

[3547] Mass spectrum: [M+H]⁺=471

[3548] d)(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-6-nitro-2-indolinone

[3549] Prepared analogously to Example 39c by catalytic hydrogenation of(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-1-hydroxy-6-nitro-2-indolinone.

[3550] Yield: 4% of theory

[3551] R_(f) value: 0.4 (silica gel; dichloromethane/methanol=9:1)

[3552] C₂₇H₂₆N₄O₃ (454.53)

[3553] Mass spectrum: [M⁺]=454

EXAMPLE 449

[3554](Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-6-bromo-2-indolinone

[3555] Prepared analogously to Example 1.

[3556] R_(f) value: 0.24 (silica gel; dichloromethane/ethanol=9:1)

[3557] C₂₇H₂₆BrN₃O (488.43)

[3558] Mass spectrum: M⁺=489/487

EXAMPLE 450

[3559](Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-bromo-2-indolinone

[3560] Prepared analogously to Example 1.

[3561] Melting point: 170° C.

[3562] C₂₇H₂₆BrN₃O (488.43)

[3563] Mass spectrum: M⁺=489/487

EXAMPLE 451

[3564](Z)-3-[-(4-(N-(2-dimethylaminoethyl)-N-methoxymethylcarbonyl-amino]-phenylamino)-1-phenyl-methylidene]-2-indolinone

[3565] Prepared analogously to Example 327.

[3566] Melting point: 246-249° C.

[3567] C₂₈H₃₀N₄O₃ (470.48)

[3568] Mass spectrum: [M+H]⁺=471

EXAMPLE 452

[3569](Z)-3-[1-(4-(N-(2-dimethylaminoethyl)-N-benzoyl-amino)-phenylamino)-1-phenyl-methylidene]-2-indolinone

[3570] Prepared analogously to Example 327.

[3571] Melting point: 272-274° C.

[3572] C₃₂H₃₀N₄O₂ (505.62)

[3573] Mass spectrum: M⁺=502

EXAMPLE 453

[3574](Z)-3-[1-(4-(N-(2-dimethylaminoethyl)-N-butylsulphonyl-amino)-phenylamino)-1-phenyl-methylidene]-2-indolinone

[3575] Prepared analogously to Example 188.

[3576] Melting point: 225-227° C.

[3577] C₂₉H₃₄N₄O₃S (518.68)

[3578] Mass spectrum: [M+H]⁺=519

EXAMPLE 454

[3579] (Z)-3-[1-(4-(N-(2-dimethylaminoethyl)-N-(p-tolylsulphonyl)-amino)-phenylamino)-1-phenyl-methylidene]-2-indolinone

[3580] Prepared analogously to Example 188.

[3581] Melting point: 213-215° C.

[3582] C₃₂H₃₂N₄O₃S (552.70)

[3583] Mass spectrum: M⁺=552

EXAMPLE 455

[3584](Z)-3-{1-[4-((2,6-dimethylpiperidino)-methyl)-1-phenyl-methylidene]-2-indolinone

[3585] Prepared analogously to Example 231.

[3586] Melting point: 215-17° C.

[3587] C₂₉H₃₁N₃O (437.58)

[3588] Mass spectrum: (M+H)⁺=438

[3589] The following compounds may be prepared analogously to thepreceding Examples:

[3590] (1)(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-methyl-2-indolinone

[3591] (2)(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-chloro-2-indolinone

[3592] (3)(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-6-methyl-2-indolinone

[3593] (4)(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-6-chloro-2-indolinone

[3594] (5)(Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-(4-methylphenyl)-methylidene}-2-indolinone

[3595] (6)(Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-(3-methylphenyl)-methylidene}-2-indolinone

[3596] (7)(Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-(3-methoxyphenyl)-methylidene}-2-indolinone

[3597] (8)(Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-(3-chlorophenyl)-methylidene}-2-indolinone

[3598] (9)(Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-(4-nitrophenyl)-methylidene}-2-indolinone

[3599] (10)(Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-(3-nitrophenyl)-methylidene}-2-indolinone

[3600] (11)(Z)-3-{1-[4-(N-(2-aminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3601] (12)(Z)-3-{1-[4-(N-(2-acetylaminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3602] (13)(Z)-3-{1-[4-(N-(2-methylaminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3603] (14)(Z)-3-{1-[4-(N-(2-(N-acetyl-N-methyl-amino)-ethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3604] (15)(Z)-3-{1-[4-(N-(2-ethylamino-ethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3605] (16)(Z)-3-{1-[4-(N-(2-(N-acetyl-N-ethyl-amino)-ethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3606] (17)(Z)-3-{1-[4-(N-diethylaminoethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3607] (18)(Z)-3-{1-[4-(N-(3-aminopropyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3608] (19)(Z)-3-{1-[4-(N-(3-aminopropyl)-N-ethylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3609] (20)(Z)-3-{1-[4-(N-(3-methylaminopropyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3610] (21)(Z)-3-{-[4-(N-(3-methylaminopropyl)-N-ethylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3611] (22)(Z)-3-{1-[4-(N-(3-aminopropyl)-N-acetyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3612] (23)(Z)-3-{1-[4-(N-(3-aminopropyl)-N-propionyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3613] (24)(Z)-3-{1-[4-(N-(3-methylaminopropyl)-N-acetyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3614] (25)(Z)-3-{1-[4-(N-(3-methylaminopropyl)-N-propionyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3615] (26)(Z)-3-{1-[4-(N-methylaminomethylcarbonyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3616] (27)(Z)-3-{1-[4-(N-(N-acetyl-N-methyl-aminomethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3617] (28)(Z)-3-{1-[4-(N-ethylaminomethylcarbonyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3618] (29)(Z)-3-{1-[4-(N-(N-acetyl-N-ethyl-aminomethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3619] (30)(Z)-3-{1-[4-(N-(2-hydroxyethyl-aminomethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3620] (31)(Z)-3-{1-[4-(N-(N-(2-hydroxyethyl)-N-methyl-aminomethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3621] (32)(Z)-3-{1-[4-(N-(N-(2-hydroxyethyl)-N-methyl-aminomethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

[3622] (33)(Z)-3-{1-[4-(N-(2-dimethylamino-ethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone

EXAMPLE 456

[3623] Dry Ampoule Containing 75 mg of Active Substance per 10 ml

[3624] Composition: Active substance 75.0 mg Mannito 150.0 mg water forinjections ad 10.0 ml

[3625] Preparation:

[3626] Active substance and mannitol are dissolved in water. Afterpackaging the solution is freeze-dried. To produce the solution readyfor use, the product is dissolved in water for injections.

EXAMPLE 457

[3627] Dry Ampoule Containing 35 mg of Active Substance per 2 ml

[3628] Composition: Active substance 35.0 mg Mannitol 100.0 mg water forinjections ad 2.0 ml

[3629] Preparation:

[3630] Active substance and mannitol are dissolved in water. Afterpackaging, the solution is freeze-dried.

[3631] To produce the solution ready for use, the product is dissolvedin water for injections.

EXAMPLE 458

[3632] Tablet Containing 50 mg of Active Substance

[3633] Composition: (1) Active substance 50.0 mg (2) Lactose 98.0 mg (3)Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesiumstearate 2.0 mg 215.0 mg

[3634] Preparation:

[3635] (1), (2) and (3) are mixed together and granulated with anaqueous solution of (4). (5) is added to the dried granulated material.From this mixture tablets are pressed, biplanar, faceted on both sidesand with a dividing notch on one side.

[3636] Diameter of the tablets: 9 mm.

EXAMPLE 459

[3637] Tablet Containing 350 mg of Active Substance

[3638] Composition: (1) Active substance 350.0 mg (2) Lactose 136.0 mg(3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesiumstearate 4.0 mg 600.0 mg

[3639] Preparation:

[3640] (1), (2) and (3) are mixed together and granulated with anaqueous solution of (4). (5) is added to the dried granulated material.From this mixture tablets are pressed, biplanar, faceted on both sidesand with a dividing notch on one side.

[3641] Diameter of the tablets: 12 mm.

EXAMPLE 460

[3642] Capsules Containing 50 mg of Active Substance

[3643] Composition: (1) Active substance 50.0 mg (2) Dried maize starch58.0 mg (3) Powdered lactose 50.0 mg (4) Magnesium stearate 2.0 mg 160.0mg

[3644] Preparation:

[3645] (1) is triturated with (3). This trituration is added to themixture of (2) and (4) with vigorous mixing.

[3646] This powder mixture is packed into size 3 hard gelatin capsulesin a capsule filling machine.

EXAMPLE 461

[3647] Capsules Containing 350 mg of Active Substance

[3648] Composition: (1) Active substance 350.0 mg (2) Dried maize starch46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium stearate 4.0 mg 430.0mg

[3649] Preparation:

[3650] (1) is triturated with (3). This trituration is added to themixture of (2) and (4) with vigorous mixing.

[3651] This powder mixture is packed into size 0 hard gelatin capsulesin a capsule filling machine.

EXAMPLE 462

[3652] Suppositories Containing 100 mg of Active Substance

[3653] 1 Suppository Contains: Active substance 100.0 mgPolyethyleneglycol (M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000)460.0 mg Polyethylenesorbitan monostearate 840.0 mg 2,000.0 mg

[3654] Preparation:

[3655] The polyethyleneglycol is melted together with polyethylenesorbitan monostearate. At 40° C. the ground active substance ishomogeneously dispersed in the melt. It is cooled to 38° C. and pouredinto slightly chilled suppository moulds.

What is claimed is:
 1. Substituted indolinones of general formula

X denotes an oxygen or sulphur atom, R₁ denotes a hydrogen atom,C₁₋₃-alkyl or hydroxy group, R₂ denotes a hydrogen, fluorine, chlorine,bromine or iodine atom, a C₁₋₃-alkyl or nitro group, R₃ denotes a phenylor naphthyl group, each of which may be mono- or disubstituted byfluorine, chlorine, bromine or iodine atoms, by C₁₋₃-alkyl, C₁₋₃-alkoxy,carboxy, cyano, trifluoromethyl, nitro, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, C₁₋₃-alkylsulphonylamino, amino-C₁₋₃-alkyl,2-carboxy-phenylcarbonylaminomethyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,C₂₋₄-alkanoylamino-C₁₋₃-alkyl,N-(C₂₋₄-alkanoyl)-C₁₋₃-alkylamino-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, carboxy-C₂₋₃-alkenyl,N-(carboxy-C₁₋₃-alkyl)-aminocarbonyl,N-(carboxy-C₁₋₃-alkyl)-N-(C₁₋₃-alkyl)-aminocarbonyl orimidazolyl-C₁₋₃-alkyl groups, while the substituents may be identical ordifferent, R₄ denotes a hydrogen atom or a C₁₋₃-alkyl group and R₅denotes a phenyl or naphthyl group optionally substituted by aC₁₋₃-alkyl group, each of which may additionally be substituted in thearomatic moiety by a fluorine, chlorine, bromine or iodine atom, by aC₁₋₃-alkyl, C₁₋₃-alkoxy, cyano, nitro or trifluoromethyl group, by aC₁₋₃-alkoxy group which is substituted by a carboxy, aminocarbonyl,C₁₋₃-alkylaminocarbonyl or di-(C₁₋₃-alkyl)-aminocarbonyl group or in the2 or 3 position by an amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,phenyl-C₁₋₃-alkylamino, N-(phenyl-C₁₋₃-alkyl)-N-(C₁₋₃-alkyl)-amino,pyrrolidino, piperidino or hexamethyleneimino group, by a C₂₋₃-alkenylgroup optionally substituted by a di-(C₁₋₃-alkyl)-amino group, which mayadditionally be substituted in the alkenyl moiety by a chlorine orbromine atom, by a C₂₋₃-alkynyl group optionally substituted by adi-(C₁₋₃-alkyl)-amino group, by a C₁₋₃-alkyl group which is substitutedby a 3- to 7-membered cycloalkyleneimino group, by a dehydropiperidino,morpholino, thiomorpholino, 1-oxido-thiomorpholino,1,1-dioxido-thiomorpholino, piperazino, N-(C₁₋₃-alkyl)-piperazino,N-(C₁₋₃-alkanoyl)-piperazino or N-(C₁₋₅-alkoxycarbonyl)-piperazinogroup, whilst the above-mentioned substituents may be substituted by aC₁₋₃-alkyl, phenyl or phenyl-C₁₋₃-alkyl group and the abovementionedpiperidino or hexamethyleneimino groups may additionally be substitutedby a C₁₋₃-alkyl group or in the 3 or 4 position by a hydroxy,C₁₋₃-alkoxy, hydroxy-C₁₋₃-alkyl, carboxy, aminocarbonyl,N-(C₁₋₃-alkyl)-aminocarbonyl or N,N-di-(C₁₋₃-alkyl)-aminocarbonyl group,by a C₁₋₃-alkyl group substituted by a hydroxy, C₁₋₃-alkoxy, carboxy orcyano group, whilst a C₁₋₃-alkyl group substituted by a carboxy groupmay additionally be substituted in the alkyl moiety by an amino orC₁₋₅-alkoxycarbonylamino group, by an aminocarbonylamino, amidino orguanidino group optionally substituted by one or two C₁₋₃-alkyl groups,by a piperidino, hexamethyleneimino, morpholino, piperazino orN-(C₁₋₃-alkyl)-piperazino group, by a formyl, carboxy or trifluoroacetylgroup, by a carbonyl group which is substituted by a C₁₋₃-alkyl,C₁₋₃-alkoxy-C₁₋₃-alkyl, amino, C₁₋₅-alkylamino or di-(C₁₋₃-alkyl)-aminogroup, while the abovementioned amino and C₁₋₃-alkylamino groups mayadditionally be substituted at the nitrogen atom by a carboxy-C₁₋₃-alkylgroup or by a C₂₋₃-alkyl group which is substituted in the 2 or 3position by a hydroxy, C₁₋₃-alkoxy, amino, C₁₋₃-alkylamino ordi-(C₁₋₃-alkyl)-amino group, by a pyrrolidinocarbonyl,piperidinocarbonyl, hexamethyleneiminocarbonyl, morpholinocarbonyl,piperazinocarbonyl, N-(C₁₋₃-alkyl)-piperazinocarbonyl orN-(phenyl-C₁₋₃-alkyl)-piperazinocarbonyl group, by an amidosulphonyl,pyrrolidinosulphonyl, piperidinosulphonyl or hexamethyleneiminosulphonylgroup, by a C₁₋₃-alkylamidosulphonyl or di-(C₁₋₃-alkyl)-amidosulphonylgroup, wherein an alkyl moiety may be substituted in each case by acarboxy, aminocarbonyl, N-(C₁₋₃-alkyl)-aminocarbonyl orN,N-di-(C₁₋₃-alkyl)-aminocarbonyl group or, in the 2 or 3 position, by aC₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-amino group, by an amino,C₁₋₅-alkylamino, C₃₋₇-cycloalkylamino, phenyl-C₁₋₃-alkylamino,phenylamino, 6-membered heteroarylamino, amino-C₁₋₃-alkyl,N-(C₁₋₅-alkyl)-amino-C₁₋₃-alkyl, di-(C₁₋₅-alkyl)-amino-C₁₋₃-alkyl,C₃₋₇-cycloalkylamino-C₁₋₃-alkyl,N-(C₁₋₅-alkyl)-C₃₋₇-cycloalkylamino-C₁₋₃-alkyl, phenylamino-C₁₋₃-alkyl,N-(C₁₋₃-alkyl)-phenylamino-C₁₋₃-alkyl, phenyl-C₁₋₃-alkylamino-C₁₋₃-alkylor N-(C₁₋₅alkyl)-phenyl-C₁₋₃-alkylamino-C₁₋₃-alkyl group or by a6-membered heteroarylamino-C₁₋₃-alkyl group optionally substituted atthe nitrogen atom by a C₁₋₅-alkyl group, while the N-alkyl moiety of theabovementioned groups may be substituted in each case by a cyano,carboxy, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl,2-[di-(C₁₋₃-alkyl)-amino]-ethylaminocarbonyl,3-[di-(C₁₋₃-alkyl)-amino]-propylaminocarbonyl,N-{2-[di-(C₁₋₃-alkyl)-amino]-ethyl}-N-(C₁₋₃-alkyl)-aminocarbonyl orN-{3-[di-(C₁₋₃-alkyl)-amino]-propyl}-N-(C₁₋₃-alkyl)-aminocarbonyl groupor in the 2 or 3 position by a hydroxy, C₁₋₃-alkoxy, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, pyrrolidino, piperidino,hexamethyleneimino, morpholino, piperazino or N-(C₁₋₃-alkyl)-piperazinogroup and the nitrogen atom of the abovementioned amino,N-(C₁₋₅-alkyl)-amino, C₃₋₇-cycloalkylamino, phenyl-C₁₋₃-alkylamino,phenylamino, 6-membered heteroarylamino, amino-C₁₋₃-alkyl- andN-(C₁₋₅-alkylamino)-C₁₋₃-alkyl groups may additionally be substituted bya C₁₋₅-alkoxycarbonyl group, by a formyl, trifluoroacetyl or benzoylgroup, by a carboxy-C₁₋₃-alkyl, aminocarbonyl-C₁₋₃-alkyl,N-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl orN,N-di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl group, by a C₁-alkyl groupwhich may be substituted, except in the 1 position, by a hydroxy,C₁₋₃-alkoxy, amino, C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-amino group, by aC₂₋₄-alkanoyl group which may be substituted in the alkanoyl moiety by acarboxy, hydroxy, C₁₋₃-alkoxy, phenyl, amino, phthalimido,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, pyrrolidino, piperidino,hexamethyleneimino or morpholino group or by a piperazino groupoptionally substituted at the nitrogen atom by a C₁₋₃-alkyl orphenyl-C₁₋₃-alkyl group, while the alkyl moiety of the abovementionedC₁₋₃-alkylamino- and di-(C₁₋₃-alkyl)-amino substituents may besubstituted in the 2 or 3 position by a hydroxy, C₁₋₃-alkoxy, amino,C₁₋₅-alkoxycarbonylamino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,phenyl, pyrrolidino, piperidino, hexamethyleneimino or morpholino group,by a C₁₋₅-alkylsulphonyl group in which the alkyl moiety may besubstituted except in the 1 position by a di-(C₁₋₃-alkyl)-amino,pyrrolidino, piperidino, hexamethyleneimino or morpholino group, by aphenyl-(C₁₋₃)-alkylsulphonyl or phenylsulphonyl group optionallysubstituted in the phenyl moiety by a fluorine, chlorine or bromine atomor by a C₁₋₃-alkyl or C₁₋₃-alkoxy group, while additionally any carboxy,amino or imino group present may be substituted by a group which can becleaved in vivo, the isomers and the salts thereof.
 2. Substitutedindolinones of general formula I according to claim 1, wherein X denotesan oxygen or sulphur atom, R₁ denotes a hydrogen atom, a C₁₋₃-alkyl,hydroxy, C₁₋₄-alkoxycarbonyl or C₂₋₄-alkanoyl group, R₂ denotes ahydrogen, fluorine, chlorine, bromine or iodine atom, a C₁₋₃-alkyl ornitro group, R₃ denotes a phenyl or naphthyl group, each of which may bemono- or disubstituted by fluorine, chlorine, bromine or iodine atoms,by C₁₋₃-alkyl, imidazolylmethyl, 2-carboxyethenyl,2-(C₁₋₃-alkoxycarbonyl)-ethenyl, C₁₋₃-alkoxy, cyano, carboxy,C₁₋₃-alkoxycarbonyl, trifluoromethyl, nitro, amino, phthalimidomethyl,2-carboxy-phenylcarbonylaminomethyl, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, C₁₋₃-alkylsulphonylamino, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, C₂₋₄-alkanoylamino-C₁₋₃-alkyl,N-(C₂₋₄-alkanoyl)-C₁₋₃-alkylamino-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, carboxy-C₁₋₃-alkylaminocarbonyl orC₁₋₃-alkoxycarbonyl-C₁₋₃-alkylaminocarbonyl groups, while thesubstituents may be identical or different, R₄ denotes a hydrogen atomor a C₁₋₃-alkyl group and R₅ denotes a phenyl or naphthyl groupoptionally substituted by a C₁₋₃-alkyl group, each of which mayadditionally be substituted in the aromatic moiety by a fluorine,chlorine, bromine or iodine atom, by a C₁₋₃-alkyl, C₁₋₃-alkoxy, cyano,nitro or trifluoromethyl group, while the abovementioned alkyl group maysimultaneously be substituted by a carboxy or C₁₋₃-alkoxycarbonyl groupand an amino or C₁₋₄-alkoxycarbonylamino group, a C₁₋₃-alkyl group whichis substituted by a 4- to 7-membered cycloalkyleneimino group, by adehydropiperidino, morpholino, thiomorpholino, 1-oxido-thiomorpholino,1,1-dioxido-thiomorpholino, piperazino orN-(C₁₋₄-alkoxycarbonyl)-piperazino group, while the abovementionedpiperidino, hexamethyleneimino, morpholino, thiomorpholino,1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino- and piperazinogroups may be substituted by a C₁₋₃-alkyl, phenyl or phenyl-C₁₋₃-alkylgroup and the abovementioned piperidino groups may additionally besubstituted by a C₁₋₃-alkyl group or in the 3 or 4 position by ahydroxy, C₁₋₃-alkoxy, hydroxy-C₁₋₃-alkyl, carboxy, aminocarbonyl,N-(C₁₋₃-alkyl)-aminocarbonyl or N,N-di-(C₁₋₃-alkyl)-aminocarbonyl group,by a C₁₋₃-alkyl group optionally substituted by a hydroxy, C₁₋₃-alkoxy,carboxy, C₁₋₃-alkoxycarbonyl or cyano group, by an aminocarbonylamino,amidino or guanidino group optionally substituted by one or twoC₁₋₃-alkyl groups, by a piperidino, hexamethyleneimino, morpholino,piperazino or N-(C₁₋₃-alkyl)-piperazino group, by a formyl, carboxy,C₁₋₃-alkoxycarbonyl or trifluoroacetyl group, by a carbonyl group whichis substituted by a C₁₋₃-alkyl, C₁₋₃-alkoxy-C₁₋₃-alkyl, amino,C₁₋₅-alkylamino or di-(C₁₋₃-alkyl)-amino group, while the abovementionedamino- and C₁₋₃-alkylamino groups may additionally be substituted at thenitrogen atom by a carboxy-C₁₋₃-alkyl or C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylgroup or by a C₂₋₃-alkyl group which may be substituted in the 2 or 3position by a hydroxy, C₁₋₃-alkoxy, amino, C₁₋₃-alkylamino ordi-(C₁₋₃-alkyl)-amino group, by a pyrrolidinocarbonyl,pyrrolidinosulphonyl, piperidinocarbonyl, hexamethyleneiminocarbonyl,morpholinocarbonyl, piperazinocarbonyl,N-(C₁₋₃-alkyl)-piperazinocarbonyl orN-(phenyl-C₁₋₃-alkyl)-piperazinocarbonyl group, by an amidosulphonyl,C₁₋₃-alkylamidosulphonyl or di-(C₁₋₃-alkyl)-amidosulphonyl group,wherein an alkyl moiety may be substituted by a carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group or in the 2 or 3 position may besubstituted by an amino, C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-amino group,by an amino, C₁₋₅-alkylamino, amino-C₁₋₃-alkyl,N-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, N-(2-hydroxyethyl)-amino-C₁₋₃-alkyl,N-(3-hydroxypropyl)-amino-C₁₋₃-alkyl, di-(C₁₋₅-alkyl)-amino-C₁₋₃-alkyl,N-(C₃₋₇-cycloalkyl)-amino-C₁₋₃-alkyl,N-(C₃₋₇-cycloalkyl)-N-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl orN-(phenyl-C₁₋₃-alkyl)-amino-C₁₋₃-alkyl group, while the N-alkyl moietyof the abovementioned groups may be substituted by a cyano, carboxy,C₁₋₃-alkylcarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl,2-[di-(C₁₋₃-alkyl)-amino]-ethylaminocarbonyl,3-[di-(C₁₋₃-alkyl)-amino]-propylaminocarbonyl,N-{2-[di-(C₁₋₃-alkyl)-amino]-ethyl}-N-(C₁₋₃-alkyl)-aminocarbonyl orN-{3-[di-(C₁₋₃-alkyl)-amino]-propyl}-N-(C₁₋₃-alkyl)-aminocarbonyl groupor may be substituted in the 2 or 3 position by a hydroxy, C₁₋₃-alkoxy,amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino or morpholino group, whilethe nitrogen atom of the abovementioned amino, C₁₋₃-alkylamino,amino-C₁₋₃-alkyl or N-(C₁₋₅-alkylamino)-C₁₋₃-alkyl moieties mayadditionally be substituted by a C₁₋₅-alkoxycarbonyl group, by a formyl,trifluoroacetyl or benzoyl group, by a C₁₋₅-alkyl group which may besubstituted, except in the 1 position, by a hydroxy, C₁₋₃-alkoxy, amino,C₁₋₃-alkylamino or di-(C₁₋₃)-alkylamino group, by a C₂₋₄-alkanoyl groupwhich may be substituted in the alkanoyl moiety by a hydroxy,C₁₋₃-alkoxy, amino, C₂₋₄-alkanoylamino, C₁₋₅-alkoxycarbonylamino,phthalimido, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,N-(C₁₋₃-alkyl)-phenylamino, pyrrolidino, piperidino or morpholino groupor by a piperazino group optionally substituted at the nitrogen atom bya C₁₋₃-alkyl or phenyl-C₁₋₃-alkyl group, while the N-alkyl moiety of theabovementioned groups may be substituted in the 2 or 3 position by amethoxy, di-(C₁₋₃-alkyl)-amino or morpholino group, by aC₁₋₅-alkylsulphonyl group in which the alkyl moiety may be substituted,except in the 1 position, by a di-(C₁₋₃-alkyl)-amino, pyrrolidino,piperidino, hexamethyleneimino or morpholino group, by a pyridinyl orpyrimidinyl group, by a phenyl, phenyl-(C₁₋₃)-alkylsulphonyl orphenylsulphonyl group optionally substituted in the phenyl moiety by aC₁₋₃-alkyl group, by a C₁₋₃-alkoxy group which is substituted by acarboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group or is substituted in the 2 or 3position by an amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,N-(C₁₋₃-alkyl)-N-(phenyl-C₁₋₃-alkyl)-amino, piperidino orhexamethyleneimino group, by a prop-1-enyl, 2-chloro-prop-1-enyl orprop-1-ynyl group which is substituted in the 3 position by adi-(C₁₋₃-alkyl)-amino group, the isomers and the salts thereof. 3.Substituted indolinones of general formula I according to claim 1,wherein X denotes an oxygen atom, R₁ denotes a hydrogen atom, aC₁₋₃-alkyl, C₁₋₄-alkoxycarbonyl or C₂₋₄-alkanoyl group, R₂ denotes ahydrogen, fluorine, chlorine, bromine or iodine atom, a C₁₋₃-alkyl ornitro group, R₃ denotes a phenyl group which may be mono- ordisubstituted by fluorine, chlorine, bromine or iodine atoms, byC₁₋₃-alkyl, trifluoromethyl, imidazolylmethyl, 2-carboxyethenyl,2-C₁₋₃-alkoxycarbonyl-ethenyl, C₁₋₃-alkoxy, cyano, carboxy,C₁₋₃-alkoxycarbonyl, nitro, amino, phthalimidomethyl,2-carboxy-benzoylaminomethyl, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,C₁₋₃-alkylsulphonylamino, amino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,C₂₋₄-alkanoylamino-C₁₋₃-alkyl,N-(C₂₋₄-alkanoyl)-C₁₋₃-alkylamino-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, carboxy-C₁₋₃-alkylaminocarbonyl orC₁₋₃-alkoxycarbonyl-C₁₋₃-alkylaminocarbonyl groups, while thesubstituents may be identical or different, R₄ denotes a hydrogen atomor a C₁₋₃-alkyl group and R₅ denotes a phenyl or naphthyl groupoptionally substituted by a C₁₋₃-alkyl group, each of which mayadditionally be substituted in the aromatic moiety by a fluorine,chlorine, bromine or iodine atom, by a C₁₋₃-alkoxy, cyano, nitro ortrifluoromethyl group, a C₁₋₃-alkyl group which is substituted by a 4-to 7-membered cycloalkyleneimino group, by a dehydropiperidino,morpholino, thiomorpholino, 1-oxido-thiomorpholino,1,1-dioxido-thiomorpholino, piperazino orN-(C₁₋₄-alkoxycarbonyl)-piperazino group, while the abovementionedpiperidino, hexamethyleneimino, morpholino and piperazino groups may besubstituted by a C₁₋₃-alkyl, phenyl or phenyl-C₁₋₃-alkyl group and theabovementioned piperidino groups may additionally be substituted by aC₁₋₃-alkyl group or may be substituted in the 3 or 4 position by ahydroxy, C₁₋₃-alkoxy, hydroxy-C₁₋₃-alkyl, carboxy, aminocarbonyl,N-(C₁₋₃-alkyl)-aminocarbonyl or N,N-di-(C₁₋₃-alkyl)-aminocarbonyl group,by a C₁₋₃-alkyl group optionally substituted by a hydroxy, C₁₋₃-alkoxy,carboxy, C₁₋₃-alkoxycarbonyl or cyano group, by an aminocarbonylamino,amidino or guanidino group optionally substituted by one or twoC₁₋₃-alkyl groups, by a piperidino, hexamethyleneimino, morpholino,piperazino or N-(C₁₋₃-alkyl)-piperazino group, by a formyl, carboxy,C₁₋₃-alkoxycarbonyl or trifluoroacetyl group, by a carbonyl group whichis substituted by a C₁₋₃-alkyl, C₁₋₃-alkoxy-C₁₋₃-alkyl, amino,C₁₋₅-alkylamino or di-(C₁₋₃-alkyl)-amino group, while the abovementionedamino and C₁₋₃-alkylamino groups may additionally be substituted at thenitrogen atom by a carboxy-C₁₋₃-alkyl, C₁₋₃-alkoxycarbonyl-C₁₋₃-alkyl orC₁₋₃-alkoxycarbonyl-C₁₋₃-alkyl group or by a C₂₋₃-alkyl group which maybe substituted in the 2 or 3 position by a hydroxy, C₁₋₃-alkoxy, amino,C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-amino group, by apyrrolidinocarbonyl, pyrrolidinosulphonyl, piperidinocarbonyl orhexamethyleneiminocarbonyl group, by an amidosulphonyl,C₁₋₃-alkylamidosulphonyl or di-(C₁₋₃-alkyl)-amidosulphonyl group,wherein an alkyl moiety may be substituted by a carboxy,C₁₋₃-alkoxycarbonyl or dimethylaminocarbonyl group or in the 2 or 3position by a dimethylamino group, by a straight-chain C₁₋₂-alkyl groupwhich is terminally substituted by an amino, benzylamino, pyridylaminoor pyrimidylamino group, by a C₁₋₄-alkylamino group in which the alkylmoiety may be substituted in position 2, 3 or 4 by a hydroxy or methoxygroup, or by a C₁₋₂-alkylamino group substituted in the C₁₋₂-alkylmoiety by a carboxy, C₁₋₃-alkoxycarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group, while in the abovementioned groupsany hydrogen atom present at the amino nitrogen atom may additionally bereplaced by a C₃₋₆-cycloalkyl group, by a C₁₋₄-alkyl group in which thealkyl moiety may be substituted in position 2, 3 or 4 by a hydroxygroup, by a C₁₋₂-alkylcarbonyl group optionally substituted by amethoxy, carboxy, C₁₋₃-alkoxycarbonyl, amino, methylamino,dimethylamino, acetylamino, C₁₋₅-alkoxycarbonylamino,N-methyl-C₁₋₅-alkoxycarbonylamino or morpholinocarbonylamino group, by aC₁₋₅-alkoxycarbonyl, C₁₋₄-alkylsulphonyl, phenylsulphonyl ortolylsulphonyl group, by a 3-dimethylaminopropyl or3-dimethylamino-prop-1-enyl group, by an ethyl group which issubstituted in the 1 position by an amino or C₁₋₅-alkoxycarbonylaminogroup, by an ethyl group which is substituted in the 2 position by anamino or C₁₋₅-alkoxycarbonylamino group and by a carboxy orC₁₋₃-alkoxycarbonyl group, by an amino or C₁₋₃-alkylamino group in whichthe alkyl moiety may be substituted by a cyano, carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, methylaminocarbonyl ordimethylaminocarbonyl group or may be substituted in the 2 or 3 positionby an amino, methylamino, dimethylamino, acetylamino,N-methyl-acetylamino or morpholino group, by anN-(C₁₋₃-alkyl)-aminocarbonyl or N-(C₁₋₃-alkyl)-methylaminocarbonyl groupoptionally substituted in the 2 or 3 position of the C₁₋₃-alkyl moietyby a dimethylamino group, while any hydrogen atom present at the aminonitrogen atom in the abovementioned groups may additionally be replacedby a formyl, trifluoroacetyl, benzoyl, C₁₋₄-alkoxycarbonyl orC₁₋₄-alkylaminocarbonyl group, by a C₂₋₄-alkanoyl group which may beterminally substituted by an amino, acetylamino,C₁₋₄-alkoxycarbonylamino, pyrrolidino, piperidino, morpholino,piperazino, 4-methylpiperazino, 4-benzylpiperazino or phthalimido groupor by a C₁₋₃-alkylamino, N-acetyl-C₁₋₃-alkyl-amino ordi-(C₁₋₃-alkyl)-amino group, while in the abovementionedC₁₋₃-alkylamino, N-acetyl-C₁₋₃-alkyl-amino- and di-(C₁₋₃-alkyl)-aminogroups any C₁₋₃-alkyl moiety may additionally be substituted by a phenylgroup or in the 2 or 3 position by a methoxy, dimethylamino ormorpholino group, by a C₁₋₄-alkylsulphonyl group in which the alkylmoiety may additionally be substituted in the 2 or 3 position by adimethylamino, piperidino or morpholino group, by a phenylsulphonyl ortoluenesulphonyl group, by a C₁₋₃-alkoxy group which is substituted by acarboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl, methylaminocarbonyl ordimethylaminocarbonyl group or is substituted in the 2 or 3 position byan amino, methylamino, dimethylamino, N-methyl-benzylamino, piperidinoor hexamethyleneimino group, by a C₁₋₃-alkylaminocarbonyl ordi-(C₁₋₃-alkyl)-aminocarbonyl group wherein a C₁₋₃-alkyl moiety may besubstituted in the 2 or 3 position by a methoxy or dimethylamino group,the isomers and the salts thereof.
 4. Substituted indolinones of generalformula I according to claim 1, wherein X denotes an oxygen atom R₁denotes a hydrogen atom, R₂ denotes a hydrogen, chlorine or bromineatom, a methyl or nitro group, R₃ denotes a phenyl group which may besubstituted by a fluorine, chlorine or bromine atom, by a methyl,methoxy, aminomethyl, acetylaminomethyl, carboxy, methoxycarbonyl orimidazolylmethyl group, R₄ denotes a hydrogen atom, R₅ denotes a phenylgroup which may be substituted by a fluorine, chlorine or bromine atom,by a methyl, methoxy, nitro, cyano or trifluoromethyl group, by a methylor ethyl group, each of which is substituted by a carboxy,C₁₋₃-alkoxycarbonyl, cyano, azetidin-1-yl, pyrrolidino, piperidino,4-phenylpiperidino, 3,6-dihydro-2H-pyridin-1-yl, hexamethyleneimino,morpholino, thiomorpholino, 1-oxido-thiomorpholino, piperazino,4-methylpiperazino or 4-acetylpiperazino group, while the abovementionedpiperidino groups may additionally be substituted by one or two methylgroups or may be substituted in the 3 or 4 position by a hydroxy,methoxy, carboxy, hydroxymethyl, C₁₋₃-alkoxycarbonyl, aminocarbonyl,methylaminocarbonyl or dimethylaminocarbonyl group, by a straight-chainC₁₋₂-alkyl group which may be terminally substituted by an amino orbenzylamino group, by a C₁₋₄-alkylamino group in which the alkyl moietyin positions 2, 3 or 4 is substituted by a hydroxy or methoxy group, bya C₁₋₂-alkylamino group substituted in the C₁₋₂-alkyl moiety by acarboxy, C₁₋₃-alkoxycarbonyl or dimethylaminocarbonyl group, while inthe abovementioned groups a hydrogen atom present at the amino nitrogenmay additionally be replaced by a C₃₋₆-cycloalkyl group, by a C₁₋₄-alkylgroup in which the alkyl moiety may be substituted in positions 2, 3 or4 by a hydroxy group, or by a C₁₋₂-alkylcarbonyl group optionallysubstituted by an amino, methylamino or dimethylamino group, by a3-dimethylamino-prop-1-enyl group, by an ethyl group which issubstituted in the 1-position by an amino or C₁₋₄-alkoxycarbonylaminogroup, by an amino or C₁₋₃-alkylamino group in which the alkyl moietymay be terminally substituted by a carboxy, aminocarbonyl,methylaminocarbonyl or dimethylaminocarbonyl group or in the 2 or 3position by an amino, methylamino, dimethylamino, acetylamino,N-acetyl-methylamino or morpholino group or by anN-(C₁₋₃-alkyl)-aminocarbonyl or N-(C₁₋₃-alkyl)-methylaminocarbonyl groupoptionally substituted in the 2 or 3 position by a dimethylamino group,while a hydrogen atom present at the amino nitrogen in theabovementioned groups may additionally be substituted by a formyl orbenzoyl group, by a C₂₋₄-alkanoyl group which may be terminallysubstituted by an amino, acetylamino, pyrrolidino, piperidino,morpholino, piperazino or 4-methylpiperazino group or by aC₁₋₃-alkylamino, N-acetyl-C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-aminogroup, while in the abovementioned C₁₋₃-alkylamino,N-acetyl-C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-amino groups a C₁₋₃-alkylmoiety may additionally be substituted in the 2 or 3 position by amethoxy, dimethylamino or morpholino group, by a C₁₋₄-alkylsulphonylgroup which may be substituted in the 2 or 3 position by a dimethylaminogroup, by a pyrrolidinosulphonyl group, an aminosulphonyl,C₁₋₃-alkylaminosulphonyl or di-(C₁₋₃-alkyl)-aminosulphonyl group,wherein in each case a C₁₋₃-alkyl moiety may be substituted by acarboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl, methylaminocarbonyl ordimethylaminocarbonyl group or, except in the 1 position, by adimethylamino group, by a C₂₋₃-alkoxy group which is substituted in the2 or 3 position by a dimethylamino or piperidino group, by anaminocarbonyl, C₁₋₃-alkylaminocarbonyl or di-(C₁₋₃-alkyl)-aminocarbonylgroup, wherein in each case the C₁₋₃-alkyl moieties may be substitutedby a methoxy or dimethylamino group, except in the 1 position, theisomers and the salts thereof.
 5. Substituted indolinones of generalformula I according to claim 1, wherein X and R₂ to R₄ are ashereinbefore defined, R₁ denotes a hydrogen atom and R₅ denotes a phenylgroup which may be substituted by a methyl or ethyl group, each of whichis substituted by an azetidin-1-yl, pyrrolidino, piperidino,hexamethyleneimino, morpholino, 1-oxido-thiomorpholino, piperazino,4-methylpiperazino or 4-acetylpiperazino group, while the abovementionedpiperidino groups may additionally be substituted by one or two methylgroups or in the 4 position may be substituted by a hydroxy, methoxy,hydroxymethyl, aminocarbonyl, methylaminocarbonyl ordimethylaminocarbonyl group, by a straight-chain C₁₋₂-alkyl group whichis terminally substituted by an amino group or by a C₁₋₃-alkylaminogroup, while the alkyl moiety of the C₁₋₃-alkylamino group may besubstituted in positions 2 or 3 by a hydroxy or methoxy group and in theabovementioned groups the hydrogen atom present at the amino nitrogenmay additionally be replaced by a C₃₋₆-cycloalkyl group, by a C₁₋₃-alkylgroup in which the alkyl moiety in positions 2 or 3 may be substitutedby a hydroxy group, or by a C₁₋₂-alkylcarbonyl group substituted by anamino, methylamino or dimethylamino group, by an ethyl group substitutedin the 1 position by an amino group, by an amino or C₁₋₃-alkylaminogroup in which the alkyl moiety may be terminally substituted by acarboxy, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl,N-(2-dimethylamino-ethyl)-aminocarbonyl orN-(2-dimethylamino-ethyl)-N-methyl-aminocarbonyl group or may besubstituted in the 2 or 3 position by an amino, methylamino,dimethylamino, acetylamino, N-acetyl-methylamino or morpholino group,while the hydrogen atom present at the amino nitrogen of theabovementioned groups may additionally be replaced by a C₂₋₄-alkanoylgroup which may be terminally substituted by an amino, acetylamino,pyrrolidino, piperidino, morpholino, piperazino or 4-methylpiperazinogroup or by a C₁₋₃-alkylamino, N-acetyl-C₁₋₃-alkylamino ordi-(C₁₋₃-alkyl)-amino group, while in the abovementionedC₁₋₃-alkylamino, N-acetyl-C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-aminogroups a C₁₋₃-alkyl moiety may additionally be substituted in the 2 or 3position by a methoxy, dimethylamino or morpholino group, by aC₁₋₄-alkylsulphonyl group which may be substituted in the 2 or 3position by a dimethylamino group, by a pyrrolidinosulphonyl group, anaminosulphonyl, C₁₋₃-alkylaminosulphonyl ordi-(C₁₋₃-alkyl)-aminosulphonyl group, wherein in each case a C₁₋₃-alkylmoiety may be substituted by a carboxy, methoxycarbonyl, aminocarbonyl,methylaminocarbonyl or dimethylaminocarbonyl group or, except in the 1position, by a dimethylamino group, by a C₁₋₃-alkoxy group substitutedin the 2 or 3 position by a dimethylamino or piperidino group, by anaminocarbonyl, C₁₋₃-alkylaminocarbonyl or di-(C₁₋₃-alkyl)-aminocarbonylgroup, wherein in each case a C₁₋₃-alkyl moiety may be substituted by amethoxy or dimethylamino group, except in the 1 position, the isomersand the salts thereof.
 6. The following compounds of general formula I:(a)(Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone,(b)(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone,(c)(Z)-3-{1-[4-(2-morpholinoethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone,(d)(Z)-3-{1-[4-(2-dimethylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinoneand (e)(Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinoneand the salts thereof.
 7. Physiologically acceptable salts of thecompounds according to claims 1 to
 6. 8. Pharmaceutical compositionscontaining a compound of general formula I according to at least one ofclaims 1 to 6 wherein R₁ denotes a hydrogen atom, a C₁₋₃-alkyl group ora prodrug group or a physiologically acceptable salt thereof, optionallytogether with one or more inert carriers and/or diluents.
 9. Use of acompound of general formula I according to at least one of claims 1 to6, wherein R₁ denotes a hydrogen atom, a C₁₋₃-alkyl group or a prodruggroup or a physiologically acceptable salt thereof, for preparing apharmaceutical composition which is suitable for treating excessive oranomalous cell proliferation.
 10. Process for preparing a pharmaceuticalcomposition according to claim 8, characterised in that a compound offormula I according to at least one of claims 1 to 6 wherein R₁ denotesa hydrogen atom, a C₁₋₃-alkyl group or a prodrug group or aphysiologically acceptable salt thereof is incorporated in one or moreinert carriers and/or diluents by a non-chemical method.
 11. Process forpreparing the compounds according to claims 1 to 7, characterised inthat a. a compound of general formula

wherein X, R₂ and R₃ are defined as in claims 1 to 6, R₆ denotes ahydrogen atom, a protecting group for the nitrogen atom of the lactamgroup or a bond to a solid phase and Z₁ denotes a halogen atom, ahydroxy, alkoxy or aralkoxy group, is reacted with an amine of generalformula

wherein R₄ and R₅ are defined as in claims 1 to 6, and if necessary anyprotecting group used for the nitrogen atom of the lactam group iscleaved, or a compound thus obtained is cleaved from a solid phase, orb. in order to prepare a compound of general formula I which contains anaminomethyl group and wherein X denotes an oxygen atom, a compound ofgeneral formula

wherein R₁ to R₄ are defined as in claims 1 to 6 and R₇ has the meaningsgiven for R₅ win claims 1 to 5, with the proviso that R₅ contains acyano group, is reduced, or c. in order to prepare a compound of generalformula I wherein R₁ denotes a hydrogen atom and X denotes an oxygenatom, a compound of general formula

wherein R₂ to R₅ are defined as in claims 1 to 6, is reduced andsubsequently, if desired, a compound of general formula I thus obtainedwhich contains an alkoxycarbonyl group is converted by hydrolysis into acorresponding carboxy compound, or a compound of general formula I thusobtained which contains an amino or alkylamino group is converted byalkylation or reductive alkylation into a corresponding alkylamino ordialkylamino compound or a compound of general formula I thus obtainedwhich contains an amino or alkylamino group is converted by acylationinto a corresponding acyl compound, or a compound of general formula Ithus obtained which contains a carboxy group is converted byesterification or amidation into a corresponding ester or aminocarbonyl,or a compound of general formula I thus obtained wherein R₃ denotes aphenyl group which contains a chlorine, bromine or iodine atom isconverted into a corresponding alkenylated compound by reacting with analkenyl compound, or a compound of general formula I thus obtainedwherein R₃ denotes a phenyl group which contains a chlorine, bromine oriodine atom is converted into a corresponding alkenylated compound byreacting with an alkynyl compound, and if necessary any protecting groupused to protect reactive groups during the reactions is cleaved or ifdesired a compound of general formula I thus obtained is subsequentlyresolved into the stereoisomers thereofor a compound of general formulaI thus obtained is converted into the salts thereof, in particular forpharmaceutical use into the physiologically acceptable salts thereofwith an inorganic or organic acid or base.